From owner-sci-resources@net.bio.net Wed Dec 14 22:00:00 1994 Path: biosci!biosci!not-for-mail From: "Karp, Robert" Newsgroups: bionet.sci-resources Subject: RFA on QTL Mapping of Alcohol-Related... Date: 14 Dec 1994 21:49:54 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 656 Sender: kristoff@net.bio.net Approved: biosci-moderator@net.bio.net Distribution: world Message-ID: <2EEF3251@SMTP2.mm.hub.nih.gov> NNTP-Posting-Host: net.bio.net Attached is a new RFA from NIAAA on QTL mapping of genes influencing alcohol-related behavior in rodents. The receipt date for an optional letter of intent is June 1, 1995, and for applications is July 19, 1995. The earliest possible award date is March 1, 1996. All potential applicants desiring further information are urged to contact me at the address shown below. Robert W. Karp Program Director, Genetics NIAAA rkarp@willco.niaaa.nih.gov DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM REQUEST FOR APPLICATIONS RFA AA-95-002 QTL MAPPING OF ALCOHOL-RELATED BEHAVIORAL TRAITS IN RODENTS DECEMBER 1994 PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research proposals to map quantitative trait loci (QTL) influencing rat and mouse behavioral traits which model human behavioral traits predisposing to alcoholism. Mapping of such QTL will permit subsequent testing of human homologues of these genes for linkage to alcoholism in human pedigrees. Such a test will help to establish which animal behavioral traits are most relevant to human alcoholism. Mapping of the QTL will also serve as a prologue to the isolation of the relevant genes and the identification of the products they encode. This approach can provide a novel route to elucidating the physiological mechanisms for predisposition to alcoholism and to developing intervention strategies to diminish harmful effects of alcohol. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2000, a PHS-led national activity for setting priority areas. This Request for Applications (RFA) is related to the priority areas of alcohol abuse reduction and alcoholism treatment. Potential applicants may obtain a copy of Healthy People 2000 (Full Report: Stock No. 017- 001-00474-0, or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, D.C. 20402-9325 (Telephone: 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic or foreign, public or private, nonprofit or for-profit organizations, such as universities, colleges, hospitals, research institutes and organizations, units of State or local governments, and eligible agencies of the Federal Government. Women and minority investigators are encouraged to apply. Foreign applicants are not eligible for First Independent Research Support and Transition (FIRST) Awards (R29). MECHANISMS OF SUPPORT Research support may be obtained through applications for a regular research grant (R01) or First Independent Research Support and Transition (FIRST) Award (R29). Applicants for R01s may request support for up to 5 years. In FY 1992, the average total cost per year for new R01s funded by NIAAA was approximately $200,000. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will vary also. FIRST Award applications must be for 5 years. Total direct costs for the 5-year period may not exceed $350,000 or $100,000 in any one budget period. FIRST Awards cannot be renewed, but grantees may apply for R01 support to continue research on the same topics. Potential applicants for FIRST Awards should obtain copies of the FIRST program announcement (revised February 1994) from the National Clearinghouse for Alcohol and Drug Information, P.O. Box 2345, Rockville, Maryland 20852, telephone: 301-468-2600 or 1-800-729-6686. Program project grant applications (P01) will not be accepted for this RFA. Applicants may submit applications for Investigator-Initiated Interactive Research Project Grants. Interactive Research Project Grants require the coordinated submission of related research project grant (R01) and, to a limited extent FIRST Award (R29) applications from investigators who wish to collaborate on research, but do not require extensive shared physical resources. These applications must share a common theme and describe the objectives and scientific importance of the interchange of, for example, ideas, data, and materials among the collaborating investigators. A minimum of two independent investigators with related research objectives may submit concurrent, collaborative, cross-referenced individual R01 and R29 applications. Applicants may be from one or several institutions. Further information on these and other grant mechanisms may be obtained from the program staff listed in the Inquiries section of this RFA. FUNDS AVAILABLE It is estimated that up to $1.1 million will be available for approximately six grants under this RFA in FY 1996. This level of support is dependent on the receipt of sufficient number of applications of high scientific merit. The funds set aside for this RFA are intended to support all aspects of projects funded, except for genotyping of the animals generated during the course of the research, which will be supported by a separately awarded contract (see SPECIAL REQUIREMENTS, below). Although this program is provided for in the financial plan of NIAAA, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. The earliest possible award date is March 1, 1996. RESEARCH OBJECTIVES Genetic Basis of Alcoholism Alcoholism has been recognized for over a century as a familially transmitted condition. Over the past 25 years, considerable evidence from family, twin, and adoption studies supports important roles for both genes and environment in its etiology in both men (Cloninger, et al., 1981; Merikangas, 1990; McGue, et al. 1992) and women (Kendler, et al. 1992). The specific etiological factors underlying susceptibility to alcoholism remain, however, unknown. Ongoing efforts to discover genes linked to alcoholism in human pedigrees are challenged by the heterogeneous, polygenic nature of alcoholism, along with the incompletely understood role of the environment in its etiology (Aston and Hill, 1990). These efforts could be greatly bolstered by a strategy taking advantage of powerful genetic methods permitting identification of genes influencing ethanol-related behavior in experimental animals (Lander and Botstein, 1989; Gora-Maslak, et al., 1991). Human homologues of these genes could then be tested directly for linkage to alcoholism in human pedigrees. The recent large increase in the density of markers on the mouse genetic map (Copeland, et al., 1993), along with the development of new and more powerful methods of data analysis (Lander and Botstein, 1989), have now made it possible to map individual quantitative trait loci (QTL), the genes contributing jointly to the determination of genetically complex traits (such as behavior) (Gora-Maslak, et al., 1991). Since mapped genes can be isolated and their encoded products characterized, QTL mapping offers a powerful reductionistic approach for dissecting the complex physiological bases of alcohol-related behavior. A detailed human-mouse synteny map can accurately predict the map location of potential human homologues of mouse genes (Nadeau, et al., 1992), so that these predicted loci can then be tested for linkage to alcoholism in human alcoholic pedigrees. This strategy would permit the direct application of knowledge gained from an animal behavior genetic study, for which behavioral measures are precisely defined and powerful genetic techniques can be brought to bear, to a human genetic study of alcoholism. A finding of linkage would, moreover, provide additional evidence for the relevance of the animal behavior under study to human alcoholism. Human Behavioral Indicators of Predisposition to Alcoholism Because family history of alcoholism is a significant risk factor for alcoholism (Cotton, 1979), researchers have examined psychological, biological, and behavioral characteristics that distinguish children of alcoholics from children of non-alcoholics as a means of identifying indicators of vulnerability to alcoholism. The most prominent theories of vulnerability to alcoholism have centered on temperament, baseline sensitivity, and acute tolerance to alcohol. Temperament models of vulnerability to alcoholism propose that deviations in dispositional traits mediate transmission of alcoholism (Tarter, 1991; Cloninger, 1987). According to Tarter, who used Rowe and Plomin's (1977) six dimensions of temperament, children at high risk for developing alcoholism have traits such as high behavioral activity, low attention span and persistence, low soothability, high emotionality, and low sociability. These disturbances of temperament in children of alcoholics are attributed to neurological dysfunction in the prefrontal, limbic, and midbrain areas. This theory is supported by observations of a number of differences between children of alcoholics and children of nonalcoholics, including increased incidence of psychopathology (attention deficit hyperactivity disorder, childhood conduct disorder, anxiety disorders and depression, antisocial personality disorder), behavioral disturbances (impulsiveness, aggression, emotionality), neuropsychological deficits (abstraction/ conceptualization, verbal ability), and neurophysiological variations (reduced amplitude of the P3 component of event- related potentials) (see Tarter, 1991; Sher, 1991 for reviews). In a similar vein, Cloninger's model of Type 1 and Type 2 alcoholism (Cloninger, 1987) is based on temperamental differences (novelty seeking, harm avoidance, reward dependence), which are related to selective neurological substrates and predispose an individual to certain types of alcoholism. For example, Type 2 alcoholics are high in novelty seeking, associated with impulsiveness, distractibility, and positively motivated drinking. Type 1 alcoholics, on the other hand, are high in harm avoidance and reward dependence associated with anxiety, shyness, emotional dependence, and negatively motivated drinking (i.e., escape from dysphoric feelings). The sensitivity hypothesis of vulnerability to alcoholism, first elaborated by Schuckit and his colleagues in the early 1980s, postulated that children of alcoholics are less sensitive to the subjective intoxicating effects of alcohol, and therefore, are susceptible to drinking excessively (Schuckit, 1980, 1984). However, subsequent studies designed to test this hypothesis demonstrated opposite effects, i.e., children of alcoholics were more sensitive to the reinforcing effects of alcohol as measured by muscle relaxing, stress-dampening, electroencephalographic and mood effects (see Sher, 1991 for review). A recent interpretation proposed by Newlin and Thomson (1990) may resolve this conflict. Compared to sons of nonalcoholic fathers, sons of alcoholic fathers show greater acute sensitivity to the reinforcing effects of alcohol (euphoria, muscle relaxation, stress-response dampening) on the ascending limb of the blood alcohol curve, and less sensitivity (greater acute tolerance) to the aversive effects of alcohol (nausea, dysphoria) on the descending limb of the blood alcohol curve. Measuring Animal Behaviors Related to Human Traits Predicting Alcoholism Investigators are now mapping QTL influencing various ethanol-related behaviors in mice, including preference for drinking, sensitivity to sedation, locomotor activation, hypothermia, and withdrawal severity (for review, see Crabbe, et al., 1994). More recently, they have begun mapping genes influencing more complex behaviors, such as acute functional tolerance to ataxia (Crabbe, et al., 1994a) and hypothermia (Crabbe, et al., 1994b), conditioned place preference (a measure of reinforcement) (Cunningham and Malott, 1994), and conditioned taste aversion (a measure of aversive effects) (Risinger and Cunningham, 1994). Aspects of more complex rodent behaviors could conceivably be homologous to human traits predisposing to alcoholism. Some of the corresponding assays could, in principle, be adapted for QTL mapping. Examples are given below. (These examples are for illustrative purposes only, and are not intended to exclude other behavioral tests from this RFA.) Tests that assess intrinsic traits of temperament or personality predisposing humans to alcoholism, such as impulsiveness, novelty seeking, aggression, hyperactivity, emotionality, anxiety, and stress reactivity, can be administered to rodents. Impulsiveness in individuals at risk for alcoholism has been attributed to prefrontal-limbic brain dysfunction (Tarter, 1991) and is comparable to difficulties in response inhibition observed in rodents with prefrontal lesions (see Kolb, 1984 for review). Evidence of impaired response inhibition in rodents has been measured by reversal learning tasks (i.e., the animal first learns to respond to a particular stimulus or location for a reward, and then must reverse its response to a different place or stimulus), tests of response extinction (a previously rewarded response is no longer rewarded), or go/no go tasks (reward is presented for responding to a stimulus on "go" trials, and for not responding on "no go" trials) (Kolb, 1984; Sakurai and Sugimoto, 1985). Animals with deficits in response inhibition have difficulty shifting responses on reversal tasks, continue responding when rewards are no longer presented, and fail to suppress responding on "no go" trials. Research on alcohol and aggression in humans and animals has focused on whether alcohol consumption increases violent/aggressive behavior toward family members, peers, or rivals (see Miczek, et al., 1993 for review). However, whether a history of antisocial personality or aggressive behavior predisposes a person to excessive alcohol consumption has received little study. Measures of aggressive behavior in rodents that might reflect aspects of human antisocial behavior include social interaction/social conflict paradigms, such as isolation-induced aggression between male pairs, resident-intruder encounters, and possibly frustration-induced aggression (omission of reward) (Cairns, et al., 1983; Miczek, et al., 1993; Brain, et al., 1993). Measures of other traits potentially serving as markers of human alcoholism, such as anxiety, emotionality, activity level, and novelty-seeking, could be applied to rodents. Novelty or "sensation-seeking" can be measured by nose-poke or hole board behavior in which the animal places its nose or head into a board with equally spaced holes. Activity level can easily be measured with activity wheels or by the number of boxes crossed in an open field. Hole board behavior and exploratory open field activity, along with number of defecations and rearings in the open field, have also been used to quantitate levels of anxiety and emotionality. Other experimental paradigms for measuring anxiety include conflict paradigms, acoustic startle response, and elevated plus-maze (see Crawley, 1985; Shepard, 1986; Heilig, et al., 1994; Stout and Weiss, 1994 for reviews of all of these paradigms). A further related behavior is stress reactivity, which could be measured by responses to various stressors (social stress, isolation, early weaning), such as changes in vocalization pattern, disruption of circadian rhythms, or autonomic responses such as changes in blood pressure or heart rate (see Pohorecky, 1990; Brown, et al., 1991 for reviews). Acute behavioral tolerance to a single challenge dose of alcohol can be demonstrated in animals by comparing the extent of functional impairment at a given blood alcohol concentration on the ascending limb of the blood alcohol curve with the extent of impairment when the same alcohol concentration is reached on the descending limb. The development of acute tolerance within a single session to alcohol's effects such as motor impairment, hypothermia, and operant responding has been shown by several studies (LeBlanc, et al., 1975; Crabbe, et al., 1994b; Le, et al., 1992; Hiltunen and Jarbe, 1992). Finally, because frequency and amount of alcohol consumed are significant discriminators of alcoholic subtypes (Babor, et al., 1992; Morley and Skinner, 1986), measures of temporal patterns of alcohol consumption in rodents may be informative behavioral markers. Using operant techniques, distinctive temporal patterns of alcohol consumption have been demonstrated in the selectively bred alcohol-preferring and -nonpreferring rats (Schwarz-Stevens, et al., 1991). Such techniques could possibly be adapted to permit QTL mapping. Methodological Considerations Most QTL mapping of behavioral traits has been done in mice because of the well- developed genetic map available for this species. However, the rat genome map is now undergoing rapid development (Yamada, et al., 1994; Serikawa et al., 1992) and has already proven suitable for QTL mapping (Lindpaintner, 1992). Because many interesting behavioral paradigms have been developed in rats to study ethanol-related behaviors, NIAAA encourages investigators studying rat behavior to respond to this RFA. While the choice of animal strains for study is an important feature of experimental design, applicants are encouraged to consider using any of a wide variety of strains, rather than confining their attention only to those already used extensively in alcohol research. Applicants are also encouraged to consider using existing batteries of recombinant inbred (RI) and recombinant congenic (RC) strains. Applicants are encouraged (when cost and experimental considerations permit) to test more than one behavioral paradigm on the same group of animals. Applicants may also wish to consider neurochemical measurements (e.g., receptor binding studies, in situ hybridization, other histological measurements) on the same group of animals. Such studies offer the prospect of a rigorous determination of genetic correlations among multiple behaviors and neurochemical parameters, as well as mapping of the genes responsible for those correlations. Some behavioral paradigms of great potential interest may be so complex as to preclude measurements on the hundreds of animals required for QTL mapping. Investigators working with such paradigms are strongly encouraged to attempt modifying them so as to permit measurements on hundreds of animals, without degrading their informativeness about the principal aspect of the behavior under study. SPECIAL REQUIREMENTS This RFA is intended to support the genetic analysis of animal behaviors not previously analyzed, in the hope that these behaviors may usefully model human traits related to predisposition to alcoholism. Investigators wishing to respond to this RFA who lack expertise in genetic analysis should seek collaboration with investigators experienced in QTL mapping, insofar as such experience will prove essential for proper study design and data analysis. To support as economically as possible the large amount of genotyping required for this research, NIAAA will award a separate contract for genotyping of animals generated by the research supported under this RFA. Awardees under this RFA who desire NIAAA funding for the genotyping of the animals they generate are expected to use the services provided under this contract. Awardees will be expected to attend one joint meeting per year in or near Washington, D.C., in order to review progress, and should request sufficient funds in their budgets to support such attendance. LETTER OF INTENT Prospective applicants are asked to submit, by June 1, 1995, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number or title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows Institute staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Mark Green, Ph.D. Chief, Extramural Project Review Branch Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 409 6000 Executive Blvd. MSC 7003 Bethesda, Maryland 20892-7003 Telephone: 301-443-4375 FAX: 301-443-6077 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, Maryland 20892, telephone 301-594-7248; and from the NIAAA program administrators named below under Inquiries. The RFA label available in the PHS (rev. 9/91) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form and the YES box must be marked. Page limits and limits on size of type are strictly enforced. Applicants for FIRST Awards (R29) are reminded that such applications must include three letters of reference. Non-conforming applications will be returned without being reviewed. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies in one package to: Division of Research Grants, NIH Westwood Building, Room 240 5333 Westbard Avenue Bethesda, Maryland 20892* * (If using express mail or overnight carrier, the zip code is 20816.) At the time of submission, two additional copies of the application must also be sent to: Mark Green, Ph.D. Chief, Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 409 MSC 7003 Bethesda, Maryland 20892-7003 Telephone: 301-443-4375 FAX: 301-443-6077 Applications must be received by July 19, 1995. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must be prepared as a revised application and include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness by the Institute. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, DRG staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Institute in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non- competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. The second level of review will be provided by the National Advisory Council on Alcohol Abuse and Alcoholism. REVIEW CRITERIA Criteria to be used in the scientific and technical merit review of alcohol research grant applications will include the following: 1. The scientific, technical, or medical significance and originality of the proposed research. 2. The appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research. 3. The adequacy of the qualifications (including level of education and training) and relevant research experience of the principal investigator and key research personnel. 4. The availability of adequate facilities, general environment for the conduct of the proposed research, other resources, and collaborative arrangements necessary for the research. 5. The reasonableness of budget estimates and duration in relation to the proposed research. 6. Where applicable, the adequacy of procedures to protect or minimize effects on animal and human subjects and the environment. The review criteria for FIRST Awards (R29) are contained in the FIRST program announcement (revised February 1994). AWARD CRITERIA Applications recommended for approval by the National Advisory Council on Alcohol Abuse and Alcoholism will be considered for funding on the basis of the overall scientific and technical merit of the proposal as determined by peer review, NIAAA programmatic needs and balance, and the availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding genetic aspects of proposed research to: Robert W. Karp, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 402 6000 Executive Boulevard MSC 7003 Bethesda, Maryland 20892-7003 Telephone: 301-443-4223 FAX: 301-594-0673 Internet: rkarp@willco.niaaa.nih.gov Direct inquiries regarding behavioral aspects of proposed research to: Ellen Witt, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 402 6000 Executive Boulevard MSC 7003 Bethesda, Maryland 20892-7003 Telephone: 301-443-4223 FAX: 301-594-0673 Internet: ewitt@willco.niaaa.nih.gov Direct inquiries regarding fiscal matters to: Joseph Weeda Chief, Grants Management Branch Office of Planning and Resource Management National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 504 6000 Executive Boulevard MSC 7003 Bethesda, Maryland 20892-7003 Telephone: 301-443-4703 FAX: 301-443-3891 Internet: jweeda@willco.niaaa.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.273. Awards are made under the authorization of the Public Health Service Act, Sections 301 and 464H, and administered under the PHS policies and Federal Regulations at Title 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency Review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. REFERENCES Aston CE, Hill SY (1990): Segregation analysis of alcoholism in families ascertained through a pair of male alcoholics. Am J Hum Genet 46:879-887. Babor TF, Hofmann M, DelBoca FK, Hesselbrock V, Meyer RE, Dolinsky ZS, Rounsaville B (1992): Types of alcoholics, I. Evidence for an empirically derived typology based on indicators of vulnerability and severity. Arch Gen Psychiatry 49:599-608. Brain PF, Miras RL, Berry MS (1993): Diversity of animal models of aggression: their impact on the putative alcohol/aggression link. J Stud Alc Supp No. 11, pp. 140-145. Brown MR, Koob GF, Rivier C (1991): Stress: Neurobiology and Neuroendocrinology. New York: Marcel Dekker. Cairns RB, MacCombie DJ, Hood KE (1983): A developmental-genetic analysis of aggressive behavior in mice: I. Behavioral outcomes. J Comp Psych 97:69-89. Cloninger CR, Bohman M, Sigvardsson (1981): Inheritance in alcohol abuse. Arch Gen Psychiatry 38:861-868. Cloninger CR (1987): Neurogenetic adaptive mechanisms in alcoholism. Science 236:410-416. Copeland NG, Jenkins NA, Gilbert DJ, Eppig JT, Maltais LJ, Miller JC, Dietrich WF, Weaver A, Lincoln SE, Steen RG, Stein LD, Nadeau JH, Lander ES (1993): A genetic linkage map of the mouse: current applications and future prospects. Science 262:57-66. Cotton NS (1979): The familial incidence of alcoholism. J Stud Alcohol 40:89-116. Crabbe JC, Belknap JK, Buck KJ (1994a): Genetic animal models of alcohol and drug abuse. Science 264:1715-1723. Crabbe JC, Belknap JK, Mitchell SR, Crawshaw LI (1994b): QTL mapping of genes influencing sensitivity and tolerance to ethanol hypothermia in mice. Alcohol Clin Exp Res 18:451, abstract no. 191. Crawley JN (1985) Exploratory behavior models of anxiety in mice. Neurosci Biobehav Rev 9:37-44. Cunningham CL, Malott DH (1994): Ethanol-induced conditioned place preference in the BXD RI strains: behavioral and QTL analyses. Alcohol Clin Exp Res 18:451, abstract no. 188. Gora-Maslak G, McClearn GE, Crabbe JC, Phillips TJ, Belknap JK, Plomin R (1991): Use of recombinant inbred strains to identify quantitative trait loci in psychopharmacology. Psychopharmacology 104:413-424. Heilig M, Koob GF, Ekman R, Britton KT (1994): Corticotropin-releasing factor and neuropeptide Y: role in emotional integration. Trends Neurosci 17:80-85. Hiltunen AJ, Jarbe TUC (1992): Acute and chronic ethanol tolerance: operant behavior in naive and ethanol tolerant rats. Psychopharmacology 107:511-516. Kendler KS, Heath AC, Neale MC, Kessler RC, Eaves LJ (1992): A population- based twin study of alcoholism in women. JAMA 268:1877-1882. Kolb B (1984): Functions of the frontal cortex of the rat: a comparative review. Brain Res Rev 8:65-98. Lander ES, Botstein D (1989): Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121:185-199. Le AD, Mana M, Quan B, Kalant H (1992): Differential development of acute tolerance to the motor impairment and anticonvulsant effects of ethanol. Psychopharmacology 109:107-111. LeBlanc AE, Kalant H, Gibbins RJ (1975): Acute tolerance to ethanol in the rat. Psychopharmacologia 41:43-46. Lindpaintner K (1992) Genetic linkage analysis in hypertension: principles and practice. J Hypertens 10:121-124. McGue M, Pickens RW, Svikis DS (1992): Sex and age effects on the inheritance of alcohol problems: A twin study. J Abnorm Psych 101:3-17. Merikangas KR (1990): The genetic epidemiology of alcoholism. Psychological Med 20:11-22. Miczek KA, Weerts EM, DeBold JF (1993): Alcohol, aggression, and violence: biobehavioral determinants. In Martin SE (ed), NIAAA Research Monograph No. 24, Alcohol and Interpersonal Violence: Fostering Multidisciplinary Perspectives. NIH Publication No. 93-3496, National Institutes of Health, Rockville, MD. Morley LC, Skinner HA (1986): Empirically derived classifications of alcohol-related problems. In Galanter M (ed), Recent Developments in Alcoholism, Vol. 5. New York: Plenum Press, pp. 145-168. Nadeau JH, Davisson MT, Doolittle DP, Grant P, Hillyard AL, Kosowsky MR, Roderick TH (1992): Comparative map for mice and humans. Mamm Genome 3:480-536. Newlin DB, Thomson JB (1990): Alcohol challenge with sons of alcoholics: a critical review and analysis. Psychological Bulletin 108:383-402. Pohorecky LA (1990): Interaction of ethanol and stress: research with experimental animals -- an update. Alcohol Alcoholism 25:263-276. Risinger FO, Cunningham CL (1994): Identification of genetic markers associated with sensitivity to ethanol-induced conditioned taste aversion. Alcohol Clin Exp Res 18:451, abstract no. 187. Rowe D, Plomin R (1977): Temperament in early childhood. J Pers Assess 41:150- 156. Sakurai Y, Sugimoto S (1985): Effects of lesions of prefrontal cortex and dorsomedial thalamus on delayed go/no-go alternation in rats. Behav Brain Res 17:213-219. Sher KJ (1991): Children of Alcoholics. Chicago: University of Chicago Press. Schuckit MA (1980): Self-rating of alcohol intoxication by young men with and without family histories of alcoholism. J Stud Alcohol 41:242-249. Schuckit MA (1984): Subjective responses to alcohol in sons of alcoholics and controls. Arch Gen Psychiatry 41:879-884. Schwarz-Stevens K, Samson HH, Tolliver GA, Lumeng L, Li TK (1991): The effects of ethanol initiation procedures on ethanol reinforced behavior in the alcohol- preferring rat. Alcoholism Clin Exp Res 15:277-285. Serikawa T, Kuramoto T, Hilbert P, Mori M, Yamada J, Dubay CJ, Lindpainter K, Ganten D, Guenet JL, Lathrop GM, et al. (1992): Rat gene mapping using PCR-analyzed microsatellites. Genetics 131:701-21. Shepard RA (1986): Neurotransmitters, anxiety, and benzodiazepines: a behavioral review. Neurosci Biobehav Rev 10:449-461. Stout JC, Weiss JM (1994): An animal model for measuring behavioral responses to anxiogenic and anxiolytic manipulations. Pharmacol Biochem Behav 47:459- 465. Tarter RE (1991): Developmental behavior-genetic perspective of alcoholism etiology. In Galanter M (ed), Recent Developments in Alcoholism, Volume 9. New York, Plenum Press, pp. 69-85. Yamada J, Kuramoto T, Serikawa T (1994): A rat genetic linkage map and comparative maps for mouse or human homologous rat genes. Mamm Genome 5:63-83. From owner-sci-resources@net.bio.net Wed Dec 14 22:00:00 1994 Path: biosci!biosci!not-for-mail From: GROUP PRESS 202-260-4355 Newsgroups: bionet.sci-resources Subject: NTC NEW PROGRAM FOR A NEW PROGRAM OF GRANTS AND FELLOWSHIPS Date: 14 Dec 1994 21:50:35 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 39 Sender: kristoff@net.bio.net Approved: biosci-moderator@net.bio.net Distribution: world Message-ID: <3colfb$39t@net.bio.net> NNTP-Posting-Host: net.bio.net FOR RELEASE: MONDAY, DECEMBER 12, 1994 The U.S. EPA today announced plans for a new program of grants and fellowships for environmental research to be carried out by U.S. universities. The new program will double the Agency's existing research grants program in fiscal 1995 with the addition of $22 million. Greater interaction with the university scientific community is an integral part of EPA's commitment to seek the best talent to develop and maintain the Agency's scientific excellence. Universities are a proven source of expertise and innovative ideas on environmental research. EPA's Office of Research and Development (ORD) will be soliciting applications from universities and not-for-profit, research-intensive institutions. EPA will work with the National Science Foundation (NSF) to jointly solicit and evaluate proposals. The augmented grants program will fund research in the areas of ecosystems, environmental technologies, global change and socio-economic issues. ORD will also seek applications from graduate students under a new fellowship program for environmentally-related studies. ORD expects to issue 100 fellowships totalling $4 to $5 million in fiscal 1995. The fellowships will provide two-year support for masters students, and three- year support for students in a doctoral program. The program was created to support the development of a new generation of experts with the training and skills to address increasingly complex environmental challenges. Solicitations for the fellowships will be issued in mid-December 1994, and solicitations for the grants will be issued in early January 1995. For additional information about these initiatives, call the EPA Office of Research and Development at 202-260-7473. R-311 From owner-sci-resources@net.bio.net Thu Dec 15 22:00:00 1994 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NSF - Summary of new documents on STIS - 4 December 1994 Date: 15 Dec 1994 22:06:25 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 164 Sender: biohelp@net.bio.net Approved: biosci-moderator@net.bio.net Distribution: world Message-ID: <3crap1$am1@net.bio.net> NNTP-Posting-Host: net.bio.net This message contains a summary of the documents added to the NSF STIS system in the previous week. Reference material concerning STIS follows the summary. ------------------------------------------------------------------------ ** NEW DOCUMENTS ON STIS ** Document Type: Form Title: FM 1030s - (Revised) GPG Summary Proposal Budget Form Sample File size (bytes): 244 STIS Filename: fm1030s Also available: fm1030s.ps Document Type: General Publication Title: NSF 94-74 Connections File size (bytes): 62742 STIS Filename: nsf9474 Document Type: News Title: TIP41118 - Media Tipsheet November 18, 1994 File size (bytes): 5174 STIS Filename: tip41118 Title: TIP41129 - Media Tipsheet November 29, 1994 File size (bytes): 5043 STIS Filename: tip41129 Document Type: Press Release Title: PR 94-71 SCIENTISTS STUDY HOW PLANTS RESPOND TO ENVIRONMENTAL SIGNALS File size (bytes): 5879 STIS Filename: pr9471 Title: PR 94-73 1994 YOUNG INVESTIGATORS AWARD RECIPIENTS File size (bytes): 67601 STIS Filename: pr9473 Also available: pr9473.doc Title: PR 94-75 NATIONAL SCIENCE BOARD APPROVES NEW $365 MILLION TOTAL PRICETAG FOR LIGO File size (bytes): 4360 STIS Filename: pr9475 Title: NSF-FUNDED RESEARCHER USES NEW MICROSCOPY TECHNIQUE TO DISCOVER HOW CELLS SYNTHESIZE PROTEINS File size (bytes): 3425 STIS Filename: pr9476 Title: MARINE SCIENTISTS BEGIN EXPEDITION TO ARABIAN SEA AND INDIAN OCEAN; AREA’S MONSOONS MAY PROVIDE CLUES TO GLOBAL CLIMATE File size (bytes): 5133 STIS Filename: pr9477 Document Type: Program Guideline Title: NSF 94-136-- State/Industry/University Cooperative Research Centers File size (bytes): 51720 STIS Filename: nsf94136 Document Type: SRS Report Title: SFFRDC94 Master Government List of Federally Funded Research and Development Centers Fiscal Year 1995 (FFRDCs) File size (bytes): 6442 STIS Filename: sffrdc94 ------------------------------------------------------------------------ ** UPDATES TO EXISTING STIS DOCUMENTS ** Document Type: Form Title: FM 1030 - (Revised) GPG Summary Proposal Budget Form File size (bytes): 235 STIS Filename: fm1030 Also available: fm1030.ps Title: GPG Package of NSF-style Smart Forms File size (bytes): 811 STIS Filename: fmgpg Also available: fmgpg.zip Title: NSF 94-3 - Grant Proposal Guide Forms Kit(Revised) File size (bytes): 1476 STIS Filename: nsf943 Also available: nsf943.zip Document Type: Letter Title: Current List of REU Sites File size (bytes): 86021 STIS Filename: reulist Title: Current List of REU Sites File size (bytes): 86021 STIS Filename: reulist Document Type: Phone Book Title: NSF Alpha Telephone File size (bytes): 96391 STIS Filename: phnalpha Title: NSF Organizational Directory File size (bytes): 99853 STIS Filename: phnorg Document Type: Program Guideline Title: NSF 94-153 -- NSF-NATO POSTDOCTORAL FELLOWSHIPS IN SCIENCE AND ENGINEERING File size (bytes): 62892 STIS Filename: nsf94153 Document Type: Recruit Title: Senior Executive Service Nationwide Vacancy Listing File size (bytes): 45058 STIS Filename: sesvac ------------------------------------------------------------------------ ** FOR YOUR REFERENCE ** ------------------------------------------------------------------------ HOW TO OBTAIN DOCUMENTS The above files can be retrieved in electronic form using the STIS system. If you don't know how to use STIS, send an E-mail message to stisinfo@nsf.gov (Internet). You will receive a copy of the STIS flyer via E-mail. If you are already using STIS, you can use the information above to retrieve these files: Documents via E-mail: Send a message to stisserve@nsf.gov (Internet). Use the "STIS Filename" shown above in the "get" command. For example, to retrieve sesvac, the text of your message should be as follows: get sesvac Anonymous FTP: FTP to stis.nsf.gov. Use the "STIS Filename" shown above to retrieve a file. For example, to retrieve sesvac, you would enter: ftp> get sesvac WAIS or Gopher: Do a word search on the filename as shown in the summary. If you want a *printed* copy of a document: Send your name and postal mailing address, and the document title and number to "pubs@nsf.gov" (Internet). If you have problems with the above procedures: Send a message to "stis@nsf.gov" (Internet). From owner-sci-resources@net.bio.net Thu Dec 15 22:00:00 1994 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NSF - Summary of new documents on STIS - 11 December 1994 Date: 15 Dec 1994 22:06:31 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 105 Sender: biohelp@net.bio.net Approved: biosci-moderator@net.bio.net Distribution: world Message-ID: <3crap8$amc@net.bio.net> NNTP-Posting-Host: net.bio.net This message contains a summary of the documents added to the NSF STIS system in the previous week. Reference material concerning STIS follows the summary. ------------------------------------------------------------------------ ** NEW DOCUMENTS ON STIS ** Document Type: News Title: TIP41202 - Media Tipsheet December 2, 1994 File size (bytes): 4124 STIS Filename: tip41202 Document Type: Press Release Title: OXYGEN A COMPONENT OF EARTH’S CORE? File size (bytes): 2043 STIS Filename: pr9478 Document Type: Recruit Title: Director, Division of Materials Research File size (bytes): 7860 STIS Filename: vep952c Title: Director, Division of Materials Research File size (bytes): 5428 STIS Filename: vep952i Title: Director, Division of Materials Research File size (bytes): 7531 STIS Filename: vep952l Title: Director, Division of Social, Behavioral and Economic Research File size (bytes): 5929 STIS Filename: vep953 Title: Chemist (Associate Program Director) File size (bytes): 4318 STIS Filename: vex951 Title: Chemist (Associate Program Director) File size (bytes): 5505 STIS Filename: vex953 Title: Program Clerk (Office Automation) File size (bytes): 6039 STIS Filename: vgs9533 Title: Secretary (Office Automation) File size (bytes): 5919 STIS Filename: vgs9534 Document Type: SRS Data Brief Title: NSF 94-314 Science & Engineering Doctorate Awards are at an All-Time High File size (bytes): 4233 STIS Filename: db94314 Title: NSF 94-326 S&E Manufacturing Jobs Down- Changes Vary Greatly by Industry and Occupation File size (bytes): 4400 STIS Filename: db94326 ------------------------------------------------------------------------ ** FOR YOUR REFERENCE ** ------------------------------------------------------------------------ HOW TO OBTAIN DOCUMENTS The above files can be retrieved in electronic form using the STIS system. If you don't know how to use STIS, send an E-mail message to stisinfo@nsf.gov (Internet). You will receive a copy of the STIS flyer via E-mail. If you are already using STIS, you can use the information above to retrieve these files: Documents via E-mail: Send a message to stisserve@nsf.gov (Internet). Use the "STIS Filename" shown above in the "get" command. For example, to retrieve db94326, the text of your message should be as follows: get db94326 Anonymous FTP: FTP to stis.nsf.gov. Use the "STIS Filename" shown above to retrieve a file. For example, to retrieve db94326, you would enter: ftp> get db94326 WAIS or Gopher: Do a word search on the filename as shown in the summary. If you want a *printed* copy of a document: Send your name and postal mailing address, and the document title and number to "pubs@nsf.gov" (Internet). If you have problems with the above procedures: Send a message to "stis@nsf.gov" (Internet). From owner-sci-resources@net.bio.net Fri Dec 16 22:00:00 1994 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NIH GUIDE - RFA AI-95-001 - V23(43) 12/09/94 Date: 16 Dec 1994 16:45:47 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 855 Sender: biohelp@net.bio.net Approved: biosci-moderator@net.bio.net Distribution: world Message-ID: <3ctcbr$a04@net.bio.net> NNTP-Posting-Host: net.bio.net $$XID RFA AI95001 AI-95-001 P1O1 *************************************** STD DIAGNOSTIC DEVELOPMENT GROUPS NIH GUIDE, Volume 23, Number 43, December 9, 1994 P.T. 34; K.W. 0715182, 0745020 RFA: AI-95-001 National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: January 9, 1995 Application Receipt Date: March 23, 1995 PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) invites applications for the establishment of Sexually Transmitted Disease (STD) Diagnostic Development Groups (SDDG) for the research development, manufacturing development, and evaluation of diagnostic tests that are simple, easy-to-use, rapid and inexpensive. The specific focus of this initiative is the development and evaluation of tests for the diagnosis of cervicitis and urethritis due to Neisseria gonorrhoeae or Chlamydia trachomatis. This solicitation for cooperative agreements is designed to encourage and support joint for-profit and non-profit research groups in development and evaluation of these diagnostic tests. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), STD Diagnostic Development Groups (SDDG), is related to the priority areas of STD and HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private organizations such as universities, colleges, hospitals, laboratories, units of State or local government, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be the Cooperative Agreement (U01), an assistance mechanism, rather than an acquisition mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of a study funded under cooperative agreement(s) are discussed later in this document under the section Terms and Conditions of Award. The total project period may not exceed five years. At this time, the NIAID is administratively limiting the duration of P01 grants to four years; this administrative limitation may change in the future. The anticipated award date is September 1995. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for awards under this RFA will be $2.0 million. In Fiscal Year 1995, the NIAID plans to fund three applications: two for diagnostic test development and one for test evaluation. Depending upon the stage of development of the diagnostic test proposed, it is anticipated that the first year development awards will range from $300,000 to $850,000 (total cost). Applications for test evaluation activities will be limited to $300,000 first-year total costs. Applicants proposing budgets larger than these amounts must obtain approval, prior to submission, from Dr. Hitchcock (see INQUIRIES below). In recognition of the highly specialized scientific expertise needed, it is anticipated that applications for test development will focus on either N. gonorrhoeae or C. trachomatis; for evaluation applications, it is anticipated that the applicants will have the capability to evaluate tests for both infections. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. The usual PHS policies governing grant administration and management will apply. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. RESEARCH OBJECTIVES Background The HIV pandemic has focused attention on STDs, both because HIV infection is a fatal STD and because other STDs are implicated as risk factors for sexual transmission of HIV. Current global estimates indicate that 14 million people are infected with HIV, the cause of Acquired Immunodeficiency Syndrome (AIDS). The majority of these infections were acquired through sexual intercourse. Unless effective prevention measures to stop sexual transmission of HIV are implemented, the number of AIDS cases will continue to grow. Several clear lines of experimental evidence indicate that STDs increase sexual transmissibility of HIV infection. Recent studies indicate that both discharge STDs (chlamydial infection, gonorrhea, and trichomoniasis) and ulcerative STDs (genital herpes, syphilis, and chancroid) increase HIV transmission. Although individual risk associated with the genital ulcer diseases appears to be higher (up to nine fold) compared to the discharge diseases (ranging from three to five fold), the higher prevalence of the discharge diseases means the population attributable risk for the discharge diseases is greater than that of the ulcerative diseases. Several mechanisms of action are likely to play a role in altered susceptibility/ infectiousness. These include disruption of mucosal epithelium (providing opportunities for bidirectional trafficking of HIV), alteration of normal (protective) flora, cellular inflammation including the recruitment of CD4+ target cells to the mucosal surface, molecular interactions between the pathogens, and immune suppression/stimulation. Significant reductions in the rates of HIV transmission are likely to result from a focused effort to control the spread of these more common STDs, particularly those due to N. gonorrhoeae or C. trachomatis. Separate and apart from the HIV epidemic, STDs cause significant morbidity and mortality and contribute greatly to increasing health care costs. In the United States in 1993, an estimated 12 million cases of STDs occurred; people less then 24 years old accounted for 64 percent of these and three million were in teenagers. In 1992, costs associated with these infections approached $6 billion. STDs disproportionately affect the female, the fetus, and the newborn. Gonococcal and chlamydial infections cause pelvic inflammatory disease, infertility, and ectopic pregnancy. These STDs adversely affect pregnancy and result in spontaneous abortion, stillbirth, chorioamnionitis, premature rupture of membranes, pre- term delivery, and postpartum endometritis. Neonatal infections include gonococcal/chlamydial conjunctivitis, which may lead to blindness, and chlamydial pneumonia, which may lead to chronic respiratory disease. The importance of STD prevention as a means to prevent HIV infection, as well as the morbidity and mortality associated with the major sequelae of STDs in women and infants, are compelling reasons for the development of simple, easy-to-use, rapid, and inexpensive diagnostic tests. These will enable effective screening and antibiotic therapy for infections caused by N. gonorrhoeae or C. trachomatis. Ideally, the needed tests would be administered to a patient without the need to obtain invasive specimens and would be so rapid that an etiological diagnosis would be obtained before the end of the clinic visit. These tests are needed for both high and low prevalence settings and therefore must have appropriate (i.e., high) sensitivity and specificity. Several new and innovative tests have recently been developed. For example, PCR and similar methods have been applied. While these tests are highly specific and sensitive, the unrelenting problem with the application of these technologies is that they are complicated, relying on sophisticated technical equipment and highly trained technical staff. Finally, it is important to highlight that the tests must be inexpensive; a manufacturing cost of less than $1.00 per test is the target. The availability of a sensitive, accurate, inexpensive test will enable/encourage screening and case finding - a critical approach to controlling these asymptomatic infections, preventing HIV infection, chronic sequelae, and decreasing health care costs. In a 1991 workshop on STD Diagnostics, co-sponsored by the National Institute of Allergy and Infectious Diseases, STD researchers and representatives from funding agencies, health care delivery agencies, and industry convened to examine the potential for and constraints on developing STD diagnostics. The participants considered the special requirements of such tests and recommended that useful STD diagnostic tests should be similar in format and simplicity to the occult fecal blood card or the urine glucose dipstick; no such STD diagnostic tests exist that have the required sensitivity and specificity. The workshop participants reviewed the available biotechnology, and concluded that the principal obstacle for the development of these tests was in the application of technological innovation to obtain appropriate tests. Recent advances and possible modifications of older diagnostic approaches may lead to tests that are useful. Most promising are inexpensive biochemical tests for enzymes and metabolites and immunodiagnostics, including antigen detection tests and serological assays, using newer, simpler formats. Research Objective and Scope The objective of this RFA is to develop and evaluate tests for gonorrhea and chlamydial infection through collaborative research between private sector and academic scientists. The collaboration will facilitate the research development, manufacturing development and evaluation of new diagnostic tests for sexually transmitted discharge diseases through original and innovative approaches focused on the antigens, nucleic acids, biochemical metabolites of and immune responses to chlamydial infection and gonorrhea. Ultimately this research should lead to commercially available diagnostic tests for gonorrhea or chlamydial infection that: o utilize a non-invasive or minimally invasive clinical sample, i.e., urine or a finger stick sample of blood would be acceptable) that requires minimal processing; o utilize stable, inexpensive, and readily available reagents; o are simple to use and provide results within 10 to 20 minutes of application of the clinical sample; o have sensitivities and specificities to detect cervicitis/urethritis due to gonorrhea and chlamydial infection comparable to culture; and o are small and simply packaged. SPECIAL REQUIREMENTS Applicants may apply for either a test development or the test evaluation award, but not both. Applicants who wish to develop tests for gonorrhea and for chlamydial infection must submit a separate application for each test development effort. Test Development The scope of test development includes all activities required to improve the basic test system such that it has the desired performance characteristics and all activities required to take the prototype test format through the complete manufacturing development phase including all steps involved in the scale up, quality control assessment, and the production of three lots of 10,000 tests. The budget should reflect this research effort. Test Evaluation The scope of test evaluation includes all activities required to determine and report the characteristics of experimental/prototype tests including: (a) determination of sensitivity and specificity of the test using a panel of prepared laboratory specimens; (b) determination of the sensitivity and specificity of the test using appropriate human clinical specimens, such as blood, urine, cervical swabs, saliva or other suitable specimens; and (c) comparison of the experimental test results to those obtained by culture of the appropriate sample from the same patient. (If the results are discrepant, a confirmatory test that is based on a different target should be used.) The budget should reflect this effort. A. Minimum Requirements Test Development: o The applicant should describe, in detail, the basic assay concept and the marker that will be used as well as the functional test system. o A description of the sensitivity and specificity of the prototype tests determined by evaluating a limited number of clinical specimens. The other characteristics of the prototypes and the appropriateness of different types of clinical specimens (e.g., urine or vaginal secretions) should be included. o If discrepancies exist between performance characteristics of the prototypes at the time of submission of the application and required characteristics of the final tests, the applicant should provide a justification and a research plan for achieving the desired characteristics in the final product. o The applicant should describe the capabilities for production of tests by a manufacturing process that can be fully validated for regulatory approval. o Plans for establishing good manufacturing procedures (GMP) standards and placing the tests on real time and accelerated stability schemes using appropriate protocols should be included by the applicant. o The applicant should include plans for the final component specifications including raw materials, work-in-progress, finished goods, and unit costing. Test Evaluation: o Applicants should describe the capability to conduct laboratory evaluations of diagnostic tests for gonorrhea and chlamydial infection using laboratory prepared and human clinical specimens and conduct "gold standard" diagnostic tests (i.e., culture) using human clinical specimens. o The applicant should describe, identify, and demonstrate access to appropriate populations as a source of clinical specimens. These populations should include: symptomatic and asymptomatic women and men with gonorrhea and/or chlamydial infection; and sub-populations with ranges in disease burden to support evaluation of chlamydial and gonococcal diagnostic tests in high, intermediate and low prevalence settings. For gonorrhea, low prevalence is defined as less than 2%, intermediate as 2-8%, and high as greater than 8%. For chlamydial infection, these are defined as less than 4%, 4-7% and greater than 7%, respectively. Additionally, NIH policies for inclusion of women and minorities in the clinical studies must be met (see STUDY POPULATIONS - Inclusion of Women and Minorities in Research involving human subjects below). o The diagnostic laboratory should have access to a minimum of 7500 subjects per year. For the purpose of determining the budget, in year 1 it is anticipated that 3000 tests will be evaluated and in years 2-5 that 7500 tests per year will be evaluated. o The applicant should include detailed examples of (1) protocols for culture and confirmatory test; (2) consent forms; (3) reports of test results and other information on test performance characteristics. o Letters of collaboration from all participating clinics/clinicians are necessary. These letters shall describe in detail the agreed upon plans for obtaining informed consent of the patients, assuring confidentiality of the patient, for the collection of additional/different samples, collecting appropriate information about the patient, and the procedures for handling, labeling, storing, and transporting the clinical samples. o Since it is theoretically possible that the requirements for the experimental or prototype tests will include application of the sample to the test format at the time of specimen collection, the abilities of the collaborating clinics/clinicians to accommodate the evaluation of the test "at the bedside" (i.e., in the clinical setting) should be described. o The applicant should include a plan for administration of the diagnostic test evaluations, specifying methods to record and report the results of the diagnostic test evaluations, to calculate the sensitivity and specificity of the tests. This may include developing the specifics of the protocols; purchasing of commercially available tests (supplies for years 1 and 2 should include the purchase of 1000 commercially available tests at $5/test); receiving and shipping of reagents and samples; coding of patients, reagents, and samples, and coordinating all of the collaborators' activities (and subcontractors', if applicable). This may also include development of an organized, complete system for entering and tracking data on test results; and documentation of the conduct of all clinical evaluations. B. Definitions 1. SEXUALLY TRANSMITTED DISEASES DIAGNOSTIC DEVELOPMENT GROUP (SDDG): In this RFA, the terms Sexually Transmitted Diseases Diagnostic Development Group, SDDG and "Group" are synonymous. An SDDG is composed of a test development awardee and the test evaluation awardee. Each SDDG will have a scientific steering committee. 2. SCIENTIFIC STEERING COMMITTEE: For each SDDG, a steering committee comprised of the Principal Investigators from the development and evaluation cooperative agreements, the NIAID Scientific Coordinator, and two to three peers from the scientific community will be established. The role of the Steering Committee is to provide direction and oversight of the Group's activities and is defined below under Terms and Conditions of Award. 3. NIAID SCIENTIFIC COORDINATOR: This is a Senior Scientist of the NIAID extramural staff who coordinates NIAID's participation in the STDG. Within NIAID, this individual oversees the entire research program on sexually transmitted diseases, maintains the overall scientific balance in NIAID's diagnostic development program commensurate with new research, field observations and emerging research opportunities, and ensures that the diagnostic development program is consistent with NIAID's missions and goals. For role in the SDDG, see NIAID Staff Responsibilities, below. C. Patent Coverage Because the discovery of innovative, non-invasive, rapid, sensitive, specific and reliable diagnostic tests to identify active infection due to N. gonorrhoeae or C. trachomatis is the goal of this effort, and since active involvement by the private sector is facilitated by the existence of adequate patent coverage, it is essential that applicants provide plans to ensure such coverage. With the potential for involvement of several institutions, the patent situation could be complicated. Each applicant for a test development award must, therefore, provide a detailed description of the approach to be used for obtaining patent coverage and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. Each applicant must provide a detailed description of the procedures to be followed for the resolution of legal problems that may develop. Attention is drawn to the reporting requirements of 35 U.S.C. Parts 200-212 and 37 CFR Part 401 or FAR 52.227-11. Instructions were also published in the NIH Guide for Grants and Contracts, Vol. 19, No. 23, June 22, 1990. Note that non- profit organizations (including universities) and small business firms retain the rights to any patent resulting from Government contracts, grants, or cooperative agreements. It is also noted that a Presidential memorandum of February 18, 1983 extended to all business concerns, regardless of size, the first option to the ownership of rights to inventions as provided in P.L. 96-517. As a result of this memorandum, the relationships among industrial organizations and other participants are simplified, since all Group members can now be full partners in the research and in any inventions resulting therefrom. The specific patenting arrangements among institutions may vary and could include joint patent ownership, exclusive licensing arrangements, etc. Applicants are encouraged to develop an arrangement that is most suitable for their own particular circumstances. Federal regulation clause 37 CFR 401 and HHS Inventions regulations at 45 CFR Parts 6 and 8 require that NIH be informed of inventions and licensing occurring under NIH funded research. Invention and licensing reports must be submitted to Extramural Invention Reports Office, Office of Extramural Research, Building 31, Room 5B41, NIH, 9000 Rockville Pike, Bethesda, MD 20892. D. Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator as well as the institutional official at the time of award. These special Terms of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is the Cooperative Agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the Cooperative Agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the study will be shared among the awardees and the NIAID Scientific Coordinator. Under the cooperative agreement, a relationship will exist between the award recipient(s) and the NIAID in which the performers of the activities (1) are responsible for the requirements and conditions described below and (2) agree to accept program assistance from the named NIAID Scientific Coordinator in achieving project objectives. Failure of an awardee to meet the performance requirements, including these special terms and conditions of award, or significant changes in the level of performance, may result in a reduction in budget, withholding of support, or suspension and/or termination of the award. 1. Awardee Rights and Responsibilities The awardee is responsible for: a. Research design and development, including definition of objectives and approaches, planning, implementation, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results. b. Establishing a mandatory Steering Committee to coordinate and manage the test development and test evaluation studies. c. Implementing the data collection strategy and methods collectively decided upon by the Steering Committee. For each study involving multiple institutions, it is the responsibility of each awardee/site to ensure that data will be collected and submitted in a timely way following such procedures as agreed to by the Steering Committee. d. Establishing mechanisms for quality control and monitoring. Awardees are responsible for ensuring the accurate and timely assessment of the progress of the study, including development of procedures to ensure that data collection and management are adequate for quality control and analysis. e. Preparing and submitting interim progress reports, when requested (not more than quarterly), to the NIAID Scientific Coordinator including, as a minimum, summary data on diagnostic test performance results. Such reports are in addition to the annual awardee noncompeting continuation progress reports. f. Establishing procedures, where applicable, for all participating institutions in coordinated awards to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects. g. Cooperating in the reporting of the study findings. The NIAID will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NIAID of pooled data and conclusions, are to be developed by the Principal Investigator or Steering Committee, as applicable. NIH policies governing possible co-authorship of publications with NIAID staff will apply in all cases. In general, to warrant co-authorship, NIAID staff must have contributed to each of following areas: (a) design of the experiments or concepts being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts. The awardee will retain custody of and have primary rights to the data developed under these awards, subject to Government right of access consistent with current HHS, PHS, and NIH policies. Contents of reports of study results are solely the responsibility of the authors and do not necessarily represent the views of NIAID. 2. NIAID Staff Responsibilities It is expected that the dominant role and prime responsibility for the activity will reside with the awardee(s) for the project as a whole. However, specific tasks and activities will be shared among the awardee(s) and the NIAID Scientific Coordinator. As required for the coordination of activities and to expedite progress, the NIAID Scientific Coordinator may designate additional NIAID staff to provide advice or assistance to the awardee(s) on specific scientific, technical, or management issues. The NIAID Scientific Coordinator shall retain overall programmatic responsibility for the award(s) and will clearly specify to the awardee(s) the name(s) and role(s) of any such additional individuals and the lines of reporting authority. a. Interacting with the principal investigator(s) on a regular basis to monitor study progress. Monitoring may include: (a) regular communications with the principal investigator and staff, (b) periodic site visits for discussions with awardee research teams, (c) observation of laboratory, manufacturing, data collection and management techniques, quality control, fiscal review, and other relevant matters, as well as (d) attendance at and participation in Scientific Steering Committee. b. Convening the first meeting of and subsequent participation in the Scientific Steering Committee that oversees study conduct. The NIAID Scientific Coordinator will be a full participant and voting member of the Scientific Steering Committee. c. Serving as a resource with respect to ongoing NIAID activities that may be relevant to the research to facilitate compatibility and avoid unnecessary duplication. d. Substantial assistance in the design and coordination of research activities for awardees including: 1. Assisting by providing advice on the management and technical performance of the investigations. 2. Providing access to and use of, when appropriate, reagents and assays, and other resources available through NIAID contractors and awardees. 3. Technical advice and assistance with meeting FDA requirements. 4. Reviewing and approving study designs to insure that they are within the scope of peer review and for adequacy of safety, human subjects, and representation of women and minorities, as required by Federal regulations. 5. Reviewing and providing advice regarding the establishment of mechanisms for quality control and study monitoring. e. Making recommendations for continued funding based on: (1) overall study progress, including study subject and/or data accrual; (2) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with terms of award and reporting requirements); and/or (3) maintenance of a high quality of research which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements. 3. Joint Responsibilities In addition to the interactions defined above, awardees and NIAID staff shall share responsibility for the organization of and participation on a Scientific Steering Committee. A Scientific Steering Committee for each SDDG organized by the Principal Investigators of a test development awardee and the test evaluation awardee and the NIAID Scientific Coordinator will be the main oversight body of the study. The steering committee will be comprised of the Principal Investigators from a development and the evaluation cooperative agreements, the NIAID Scientific Coordinator, and two to three peers from the scientific community. The peers from the scientific community shall be selected jointly by the Principal Investigators and the NIAID Scientific Coordinator. The Steering Committee has primary responsibility to design joint research activities, establish priorities, develop common methods and procedures including data recording forms, establish and maintain quality control among awardees, review progress, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NIAID Scientific Coordinator and will provide periodic supplementary reports upon NIAID request. An initial meeting of the Steering Committee will be convened early after award by the NIAID Scientific Coordinator. The final structure of the Steering Committee will be established at the first meeting. The NIAID Program Officer will have voting membership on the Steering Committee. After the initial meeting, the Steering Committee will meet 1-2 times per year. A Chairperson, other than the NIAID Program Officer, will be selected by vote of the members. The Chairperson is responsible for coordinating the Committee activities, for preparing meeting agendas, for scheduling and chairing meetings, and for preparing and disseminating a concise summary of each meeting to members of the Committee. 4. Arbitration Process Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members -- one awardee designee, one NIAID designee, and a third designee with expertise in the relevant area and chosen by the other two. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, March 18, 1994, Volume 23, Number 11. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by January 9 1995, a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, the number and title of this RFA, and a list of the key investigators and their institution(s). Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Olivia Preble at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/594-7248; and from the program administrator listed under INQUIRIES. Applications must address the items stated in the section "SPECIAL REQUIREMENTS" above and must specifically agree to the Terms and Conditions of Award presented in the SPECIAL REQUIREMENTS section. Should the Group wish to place all inventions and discoveries resulting from these studies within the public domain, a letter to that effect must be submitted to Dr. Hitchcock in lieu of the patent agreement prior to submission of the application. The letter must be co-signed by the Principal Investigator and each of the business officials representing the respective institutions. The RFA label available in the PHS 398 (rev. 9/91) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-spaced photocopies in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, also submit two additional exact copies of the application, and five sets of the appendix and reprints directly to Dr. Olivia Preble at the address listed under INQUIRIES. Applications must be received by March 23, 1995. If an application is received after that date, it will be returned to the applicant without review. The DRG will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by the NIAID. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, DRG will return the application to the applicant. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non- competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be promptly notified. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. Review Criteria Based on the PURPOSE, RESEARCH OBJECTIVES, and SPECIAL REQUIREMENTS of this Request for Applications, the following review criteria will apply: o scientific, technical, and manufacturing merit or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental/methodological and manufacturing approaches proposed to carry out the research; o qualifications and research/manufacturing experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Awards will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. It is anticipated that one award will be made for test development for gonorrhoea, one award will be made for test development for chlamydial infection, and one award will be made for evaluation of tests. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Penelope J. Hitchcock Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Solar Building, Room 3A16 6003 Executive Boulevard Bethesda, MD 20892-7630 Telephone: (301) 402-0443 FAX: (301) 402-0659 or 1456 Email: penny@exec.niaid.pc.niaid.nih.gov Direct letters of intent, and inquiries regarding application preparation and review to: Dr. Olivia T. Preble Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C16 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-0818 FAX: (301) 402-2638 Email: olivia preble@exec.niaid.pc.niaid.nih.gov Direct inquiries regarding fiscal matters to: Ms. Sharie Bernard Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B22 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7075 FAX: (301) 480-3780 Email: sharie bernard@exec.niaid.pc.niaid.nih.gov Schedule Letter of Intent Receipt Date: January 9, 1995 Application Receipt Date: March 23, 1995 Scientific Review Date: July 1995 Advisory Council Date: September 1995 Anticipated Award Date: September 1995 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.856 - Microbiology and Infectious Diseases Research and No. 93.855 - Immunology, Allergic and Immunologic Diseases Research. Awards will be made under the authority of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Parts 52 and 45 CFR Part 74 [and Part 92 when applicable for State and Local governments]. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. From owner-sci-resources@net.bio.net Fri Dec 16 22:00:00 1994 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NIH GUIDE - RFA HL-95-014 - V23(43) 12/09/94 Date: 16 Dec 1994 16:45:39 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 519 Sender: biohelp@net.bio.net Approved: biosci-moderator@net.bio.net Distribution: world Message-ID: <3ctcbj$9vb@net.bio.net> NNTP-Posting-Host: net.bio.net $$XID RFA HL95014 HL-95-014 P1O1 *************************************** GENETIC MAP AND LARGE INSERT LIBRARY FOR THE RAT GENOME NIH GUIDE, Volume 23, Number 43, December 9, 1994 RFA: HL-95-014 P.T. 34; K.W. 1002019, 0755044 National Heart, Lung and Blood Institute National Center for Human Genome Research National Cancer Institute National Institute of Mental Health National Institute of Child Health and Human Development National Institute of Diabetes and Digestive and Kidney Diseases National Center for Research Resources National Institute on Drug Abuse National Institute on Alcohol Abuse and Alcoholism National Institute on Deafness and Other Communication Disorders National Institute of Dental Research National Institute of Environmental Health Sciences Letter of Intent Receipt Date: February 15, 1995 Application Receipt Date: March 15, 1995 PURPOSE The purpose of this Request for Application (RFA) is to solicit applications to construct a genetic map of the rat genome with a resolution of 0.43 cM or better and a large-insert DNA clone library of rat genomic DNA. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Genetic Map and Large Insert Library for the Rat Genome, is related to many priority areas. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications from social/ethnic minority individuals, women, and persons with disabilities are encouraged. Applications from foreign institutions will not be accepted. However, subcontracts to foreign institutions are allowable, with sufficient justification. Collaborations and consortia are encouraged. In such collaborations, the respective contributions should be well-integrated into the design of the application to encourage cross-fertilization of ideas and rapid application of the research to practical purposes. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research grant (R01) mechanism. The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is September 30, 1995. This RFA is a one-time solicitation. This RFA is an initiative of the Institutes and Centers listed above. However, the awards will be made by the National Heart, Lung, and Blood Institute (NHLBI) and managed through the NHLBI with the collaboration of the participating Institutes and Centers. FUNDS AVAILABLE A maximum of about $11.06 million (including direct and indirect costs) over a five year period will be awarded. Approximately $3.2 million may be available for the first year, $2.4 million for the second year, $1.82 million for the third year, $1.82 million for the fourth year, and $1.82 million for the fifth year. Funding is subject to the availability of funds. It is anticipated that one to two awards will be made. Applications for building either the genetic map or the large insert clone library alone will be accepted, as well as those proposing to accomplish both aims of this RFA. RESEARCH OBJECTIVES Background For many years, the rat has been an important experimental model for studying human diseases such as hypertension, cancer, behavioral disorders, diabetes, drug abuse, alcoholism, cranio-facial and dental disorders, and obesity, among others. The rat offers many advantages in this regard because of the existing body of knowledge about physiological mechanisms, the ease of breeding, and the ability to generate inbred congenic rat strains. Because of its large size in comparison with the mouse, the rat is widely used in studies of anatomy, physiology and pharmacology of the chemical senses and more generally, of intricate neuronal pathways in the brain. The usefulness of the rat as a model system is hampered, however, by the lack of high-resolution genetic and physical maps of the rat genome. A number of groups working with the rat as a model system have constructed useful genetic maps, but only in genomic regions of interest. Investigators attempting to locate particular genes in an unmapped region must construct detailed maps, thus slowing the progress of their research. Such extensive individual mapping efforts would no longer be required if a high resolution genetic map were available. The technology to construct such maps has been developed through efforts that have developed 5,000 marker genetic maps of the human and mouse genomes respectively. This technology can now be applied in a cost-effective and efficient way to construct maps of the genomes of other mammals. Similar progress has also been made in the technology for building another genomic resource that is useful in gene analysis, a large insert clone library. A number of vectors have been developed for making libraries of large DNA fragments. Additionally, there is considerable information about the depth of coverage needed to maximize the usefulness of a clone library and the best ways to format it for wide usage. The present initiative, to build a genetic map and a large-insert clone library for the rat genome, is intended to take advantage of recent technological advances and experience in mapping and library construction in order to begin constructing mapping resources of use for studies involving the rat. Objectives and Scope The first objective of this RFA is to solicit applications for research projects that will use state-of-the-art methods, and will develop any necessary new technologies, to construct a genetic map of the rat genome consisting of 6,000 easy-to-use polymorphic markers, and to do so rapidly, efficiently and at low cost. Applications are also being sought to construct a high quality, large-insert clone library of the rat genome that can be generally used by many investigators as a physical resource for obtaining DNA in any region of interest. Applications submitted in response to this RFA to accomplish either one or both of these goals will be investigator-initiated and should be forward-thinking, proposing a project design that will rapidly incorporate new approaches to map and library construction. In developing the research strategy, applicants should consider and address the following: Construction of the Genetic Map The rat strains to be used for constructing the map. As this RFA is an interdisciplinary effort involving several of the Institutes and Centers of the NIH, rat strains that will be most useful to the widest community of researchers should be selected. A clear justification for selection of the strains and how they will be used must be presented. After the map has been constructed, applicants may wish to consider genotyping the one available battery of recombinant inbred rats (J. Kunes and J. Zicha, Physiol Res 42:225-233, 1993) with a subset of markers at intervals of 5 cM or less; The strategy for map construction. The completed map should consist of at least 6,000 polymorphic markers displaying a high degree of variation among strains that are commonly used in biomedical research, yielding a map of 0.43 cM or less average resolution. The research plan should include a rationale for the type of marker that will be used, the number of markers that will be mapped at high odds and a realistic and well-justified estimate of the unit cost for making and mapping a genetic marker in the rat. Although the human and mouse genetic mapping efforts have been highly successful in making maps of microsatellite repeats, applications for this RFA are not limited microsatellites. Other types of markers are currently being developed and a plan to build a useful map of the rat genome using such markers would be appropriate as long as completion of a high quality, widely useful genetic map of the rat that meets the criteria described above is a reasonable expectation during the five- year period of the proposed grant and the technology for assaying the markers is or can be economically made available to the rat research community. The current status of the rat genome map should be discussed and the possibility of integrating existing markers addressed. The overall mapping plan must include a discussion of expected, quantifiable milestones that can be used to assess yearly progress, e.g., the number of markers that can be generated and mapped each year; Data management. Projects of this magnitude require informatics support for management of the data and map construction. A thorough description of the informatics plan for the project will be critical in evaluation of the proposal. Construction of a Large Insert Library The strategy for construction of a large insert clone library. Selection of the vector and source of DNA with which this library will be built should be justified in terms of its usefulness to research employing the rat model. Issues of library depth, representation, and format should also be discussed. Prior experience in building such libraries and the rationale for the strategy selected should be thoroughly discussed. Data and Resource Sharing Plans for the availability and distribution of the data and resources developed through the grant. The sharing of materials and data in a timely manner has been an essential element in the rapid progress made in construction and use of the human and mouse genetic maps. Public Health Service (PHS) policy requires that investigators make the results and accomplishments of funded activities publicly available. The advisors to the NIH and the DOE genome programs have developed a set of "NIH-DOE Guidelines for Access to Mapping and Sequencing Data and Material Resources" that address the special needs of genome research. These guidelines call for material and information from genome research to be made available within six months of the time the data or materials are generated; more rapid sharing is encouraged and has become the norm in the genome community. Applications submitted in response to this RFA should include detailed plans for sharing data and materials generated through the grant. Where appropriate, grantees may work with the private sector in making unique resources available to the larger biomedical research community at a reasonable cost. The plans proposed for sharing and data release will be reviewed for adequacy by NIH staff prior to award of the grant and the proposed sharing plan will be made a condition of the award. Investigators may request funds to defray the costs of sharing materials or submitting data in their application. Such requests must be adequately justified. Post-award Management During the course of the grant period, mapping and cloning technologies will improve, genomic technologies will evolve, and the rate of progress and focus of work supported by the grant(s) may change. It is expected that the Principal Investigator will make any necessary adjustment in scientific direction to accommodate the changing environment. In order to ensure that the project(s) remains focused on appropriate goals, incorporates new technological advances and makes sufficient progress, scientific and programmatic visits to the grantee will be conducted at a frequency to be negotiated with the awardee. In addition, Applications should include travel funds for the P.I. and the other investigators in the grant to meet yearly with NIH staff in the Washington area. LETTER OF INTENT Prospective applicants are asked to submit, by February 15, 1995, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Any applicant planning to submit an application for more than $500,000 direct cost per year must have contacted one of the NIH staff listed under INQUIRIES before submitting the application or it will be returned to the applicant. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows IC staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 557 Bethesda, MD 20892 Telephone: (301) 594-7478 FAX: (301) 594-7407 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/594-7248. The RFA label available in the PHS 398 (rev. 9/91) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to Dr. Scheirer at the address listed under INQUIRIES. Applications must be received by March 15, 1995. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness to the RFA by NIH program staff. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NIH staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NHLBI and the NCHGR. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. All applicants will receive a summary statement consisting of the reviewer's written comments essentially unedited. Summary Statements for competitive applications will also contain a summary of the review committee's discussion. The second level of review will be provided by the National Heart, Lung, and Blood Advisory Council and by the National Advisory Councils/Boards of the other Institutes and Centers involved. Review criteria will include the following: o scientific and technical merit of the research proposed to meet the objectives of this RFA; o the value of the proposed map to the scientific community; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources and technology necessary to perform the research; o adequacy of facilities and resources and the level of institutional commitment; o appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The anticipated date of award is September 30, 1995. Factors that will be used to make award decisions are as follows: o Quality of the proposed project as determined by peer review; o Promise of the proposed program to accomplish the goals of this RFA and address the needs of the participating Institutes and Centers as regards their interest in the rat as a model organism; o Nature and extent of the plans for sharing distributing data and resources in a timely manner; o Availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Stephen C. Mockrin, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Federal Building, Room 4C10 7550 Wisconsin Avenue Bethesda, MD 20892 Telephone: (301) 496-1613 FAX: (301)402-2044 Email: SM60d@nih.gov Jane L. Peterson, Ph.D. Mammalian Genomics Branch National Center for Human Genome Research Building 38A, Room 610, MSC 6050 Bethesda, MD 20892-6050 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: jane_peterson@occhost.nlm.nih.gov Grace L. Shen, Ph.D, Hematology and Oncology for Extramural Program National Cancer Institute Executive Plaza North, Room 501 6130 Executive Boulevard, MSC 7381 Rockville, MD 20892-8531 Telephone: (301) 496-7815 FAX: (301) 496-8656 Email: sheng@dcbdcep.nci.nih.gov Ljubisa Vitkovic, Ph.D. Division of Neuroscience and Behavioral Science National Institute of Mental Health 5600 Fishers Lane, Room 11C-06 Rockville, MD 20857 Telephone: (301) 443-5288 FAX: (301) 443-4822 Email: lv5@cu.nih.gov Steven Kaminsky, Ph.D. Developmental Biology Genetics and Teratology Branch National Institute of Child Health and Human Development Building 61E, Room 4B01D, MSC 6050 Bethesda, MD 20892-6050 Telephone: (301) 496-5541 FAX: (301) 402-4083 Email: tky@cu.nih.gov Joan T. Harmon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN-18G, MSC 6401 Bethesda, MD 20892-6401 Telephone: (301) 594-7565 FAX: (301) 594-9011 Email: joanh@dvsgate.niddk.nih.gov Louise Ramm, Ph.D. Deputy Director National Center for Research Resources Building 12A, Room 4009, MSC 5662 Bethesda, MD 20892-5662 Telephone: (301) 496-6023 or (301) 594-7906 FAX: (301) 402-0006 Email: louiser@ep.ncrr.nih.gov Theresa Lee, Ph.D. Division of Basic Research National Institute on Drug Abuse 5600 Fishers Lane, Room 10A-19 Rockville, MD 20857 Telephone: (301) 443-6300 FAX: (301) 594-6043 Email: tlee@aoada.ssw.dhhs.gov Robert Karp, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4223 FAX: (301) 594-0673 Email: rkarp@willco.niaaa.nih.gov Ralph F. Naunton, M.D. Division of Human Communication National Institute on Deafness and Other Communication Disorders Executive Plaza South, Suite 400C 6120 Executive Boulevard, MSC 7180 Rockville, MD 20892-7180 Telephone: (301) 496-1804 FAX: (301) 402-6251 Email: nauntonr%nidcd-eps%nih@fedtcp.ninds.nih.gov Norman S. Braveman, Ph.D. Assistant Director for Program Development National Institute of Dental Research Building 45, Room 4AN24B, MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-2089 FAX: (301) 480-8381 Email: bravemann@de45.nidr.nih.gov William A. Suk, Ph.D., M.P.H. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-0797 FAX: (919) 541-2843 Email: suk@niehs.nih.gov Direct inquiries regarding fiscal matters to: Mr. Thomas G. Turley Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A12B Bethesda, MD 20892 Telephone: (301) 594-7434 FAX: (301) 594-7492 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837, Heart and Vascular Diseases. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. From owner-sci-resources@net.bio.net Fri Dec 16 22:00:00 1994 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NIH GUIDE - RFA AA-95-002 - V23(43) 12/09/94 Date: 16 Dec 1994 16:45:33 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 707 Sender: biohelp@net.bio.net Approved: biosci-moderator@net.bio.net Distribution: world Message-ID: <3ctcbd$9ui@net.bio.net> NNTP-Posting-Host: net.bio.net $$XID RFA AA95002 AA-95-002 P1O1 *************************************** QTL MAPPING OF ALCOHOL-RELATED BEHAVIORAL TRAITS IN RODENTS NIH GUIDE, Volume 23, Number 43, December 9, 1994 RFA: AA-95-002 P.T. 34; K.W. 0404003, 0414015, 1002019 National Institute on Alcohol Abuse and Alcoholism Letter of Intent Receipt Date: June 1, 1995 Application Receipt Date: July 19, 1995 PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research applications to map quantitative trait loci (QTL) influencing rat and mouse behavioral traits that model human behavioral traits predisposing to alcoholism. Mapping of such QTL will permit subsequent testing of human homologues of these genes for linkage to alcoholism in human pedigrees. Such a test will help to establish which animal behavioral traits are most relevant to human alcoholism. Mapping of the QTL will also serve as a prologue to the isolation of the relevant genes and the identification of the products they encode. This approach can provide a novel route to elucidating the physiological mechanisms for predisposition to alcoholism and to developing intervention strategies to diminish harmful effects of alcohol. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), QTL Mapping of Alcohol-Related Behavioral Traits in Rodents, is related to the priority areas of alcohol abuse reduction and alcoholism treatment. Potential applicants may obtain a copy of Healthy People 2000 (Full Report: Stock No. 017-001-00474-0, or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Foreign applicants are not eligible for First Independent Research Support and Transition (FIRST) (R29) Awards. MECHANISMS OF SUPPORT Research support may be obtained through applications for a regular research grant (R01) or FIRST (R29) Award. Applicants for R01s may request support for up to five years. In FY 1994, the average total cost per year for new R01s funded by the NIAAA was approximately $200,000. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will vary also. FIRST Award applications must be for five years. Total direct costs for the five-year period may not exceed $350,000 or $100,000 in any one budget period. FIRST Awards cannot be renewed, but grantees may apply for R01 support to continue research on the same topics. Potential applicants for FIRST Awards should obtain copies of the FIRST program announcement (revised February 1994) from the National Clearinghouse for Alcohol and Drug Information, P.O. Box 2345, Rockville, Maryland 20852, telephone: 301-468-2600 or 1-800-729-6686. Program project grant applications (P01) will not be accepted for this RFA. Applicants may submit applications for Investigator-Initiated Interactive Research Project Grants (IRPG) (refer to PA-94-086, Vol. 23, No. 28, July 29, 1994). Interactive Research Project Grants require the coordinated submission of related research project grant (R01) and, to a limited extent FIRST Award (R29) applications from investigators who wish to collaborate on research, but do not require extensive shared physical resources. These applications must share a common theme and describe the objectives and scientific importance of the interchange of, for example, ideas, data, and materials among the collaborating investigators. A minimum of two independent investigators with related research objectives may submit concurrent, collaborative, cross-referenced individual R01 and R29 applications. Applicants may be from one or several institutions. Further information on these and other grant mechanisms may be obtained from the program staff listed under INQUIRIES. FUNDS AVAILABLE It is estimated that up to $1.1 million in total costs will be available for approximately six grants under this RFA in FY 1996. This level of support is dependent on the receipt of sufficient number of applications of high scientific merit. The funds set aside for this RFA are intended to support all aspects of projects funded, except for genotyping of the animals generated during the course of the research, which will be supported by a separately awarded contract (see SPECIAL REQUIREMENTS, below). Although this program is provided for in the financial plan of NIAAA, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. The earliest possible award date is March 1, 1996. RESEARCH OBJECTIVES Genetic Basis of Alcoholism Alcoholism has been recognized for over a century as a familially transmitted condition. Over the past 25 years, considerable evidence from family, twin, and adoption studies supports important roles for both genes and environment in its etiology in both men (Cloninger, et al., 1981; Merikangas, 1990; McGue, et al. 1992) and women (Kendler, et al. 1992). The specific etiological factors underlying susceptibility to alcoholism, however, remain unknown. Ongoing efforts to discover genes linked to alcoholism in human pedigrees are challenged by the heterogeneous, polygenic nature of alcoholism, along with the incompletely understood role of the environment in its etiology (Aston and Hill, 1990). These efforts could be greatly bolstered by a strategy taking advantage of powerful genetic methods permitting identification of genes influencing ethanol-related behavior in experimental animals (Lander and Botstein, 1989; Gora- Maslak, et al., 1991). Human homologues of these genes could then be tested directly for linkage to alcoholism in human pedigrees. The recent large increase in the density of markers on the mouse genetic map (Copeland, et al., 1993), along with the development of new and more powerful methods of data analysis (Lander and Botstein, 1989), have now made it possible to map individual quantitative trait loci (QTL), the genes contributing jointly to the determination of genetically complex traits (such as behavior) (Gora-Maslak, et al., 1991). Since mapped genes can be isolated and their encoded products characterized, QTL mapping offers a powerful reductionistic approach for dissecting the complex physiological bases of alcohol-related behavior. A detailed human-mouse syntony map can accurately predict the map location of potential human homologues of mouse genes (Nadeau, et al., 1992), so that these predicted loci can then be tested for linkage to alcoholism in human alcoholic pedigrees. This strategy would permit the direct application of knowledge gained from an animal behavior genetic study, for which behavioral measures are precisely defined and powerful genetic techniques can be brought to bear, to a human genetic study of alcoholism. A finding of linkage would, moreover, provide additional evidence for the relevance of the animal behavior under study to human alcoholism. Human Behavioral Indicators of Predisposition to Alcoholism Because family history of alcoholism is a significant risk factor for alcoholism (Cotton, 1979), researchers have examined psychological, biological, and behavioral characteristics that distinguish children of alcoholics from children of non-alcoholics as a means of identifying indicators of vulnerability to alcoholism. The most prominent theories of vulnerability to alcoholism have centered on temperament, baseline sensitivity, and acute tolerance to alcohol. Temperament models of vulnerability to alcoholism propose that deviations in dispositional traits mediate transmission of alcoholism (Tarter, 1991; Cloninger, 1987). According to Tarter, who used Rowe and Plomin's (1977) six dimensions of temperament, children at high risk for developing alcoholism have traits such as high behavioral activity, low attention span and persistence, low soothability, high emotionality, and low sociability. These disturbances of temperament in children of alcoholics are attributed to neurological dysfunction in the prefrontal, limbic, and midbrain areas. This theory is supported by observations of a number of differences between children of alcoholics and children of nonalcoholics, including increased incidence of psychopathology (attention deficit hyperactivity disorder, childhood conduct disorder, anxiety disorders and depression, antisocial personality disorder), behavioral disturbances (impulsiveness, aggression, emotionality), neuropsychological deficits (abstraction/conceptualization, verbal ability), and neurophysiological variations (reduced amplitude of the P3 component of event-related potentials) (see Tarter, 1991; Sher, 1991 for reviews). In a similar vein, Cloninger's model of Type 1 and Type 2 alcoholism (Cloninger, 1987) is based on temperamental differences (novelty seeking, harm avoidance, reward dependence), which are related to selective neurological substrates and predispose an individual to certain types of alcoholism. For example, Type 2 alcoholics are high in novelty seeking, associated with impulsiveness, distractibility, and positively motivated drinking. Type 1 alcoholics, on the other hand, are high in harm avoidance and reward dependence associated with anxiety, shyness, emotional dependence, and negatively motivated drinking (i.e., escape from dysphoric feelings). The sensitivity hypothesis of vulnerability to alcoholism, first elaborated by Schuckit and his colleagues in the early 1980s, postulated that children of alcoholics are less sensitive to the subjective intoxicating effects of alcohol, and therefore, are susceptible to drinking excessively (Schuckit, 1980, 1984). However, subsequent studies designed to test this hypothesis demonstrated opposite effects, i.e., children of alcoholics were more sensitive to the reinforcing effects of alcohol as measured by muscle relaxing, stress-dampening, electroencephalographic and mood effects (see Sher, 1991 for review). A recent interpretation proposed by Newlin and Thomson (1990) may resolve this conflict. Compared to sons of nonalcoholic fathers, sons of alcoholic fathers show greater acute sensitivity to the reinforcing effects of alcohol (euphoria, muscle relaxation, stress-response dampening) on the ascending limb of the blood alcohol curve, and less sensitivity (greater acute tolerance) to the aversive effects of alcohol (nausea, dysphoria) on the descending limb of the blood alcohol curve. Measuring Animal Behaviors Related to Human Traits Predicting Alcoholism Investigators are now mapping QTL influencing various ethanol-related behaviors in mice, including preference for drinking, sensitivity to sedation, locomotor activation, hypothermia, and withdrawal severity (for review, see Crabbe, et al., 1994). More recently, they have begun mapping genes influencing more complex behaviors, such as acute functional tolerance to ataxia (Crabbe, et al., 1994a) and hypothermia (Crabbe, et al., 1994b), conditioned place preference (a measure of reinforcement) (Cunningham and Malott, 1994), and conditioned taste aversion (a measure of aversive effects) (Risinger and Cunningham, 1994). Aspects of more complex rodent behaviors could conceivably be homologous to human traits predisposing to alcoholism. Some of the corresponding assays could, in principle, be adapted for QTL mapping. Examples are given below. (These examples are for illustrative purposes only, and are not intended to exclude other behavioral tests from this RFA.) Tests that assess intrinsic traits of temperament or personality predisposing humans to alcoholism, such as impulsiveness, novelty seeking, aggression, hyperactivity, emotionality, anxiety, and stress reactivity, can be administered to rodents. Impulsiveness in individuals at risk for alcoholism has been attributed to prefrontal- limbic brain dysfunction (Tarter, 1991) and is comparable to difficulties in response inhibition observed in rodents with prefrontal lesions (see Kolb, 1984 for review). Evidence of impaired response inhibition in rodents has been measured by reversal learning tasks (i.e., the animal first learns to respond to a particular stimulus or location for a reward, and then must reverse its response to a different place or stimulus), tests of response extinction (a previously rewarded response is no longer rewarded), or go/no go tasks (reward is presented for responding to a stimulus on "go" trials, and for not responding on "no go" trials) (Kolb, 1984; Sakurai and Sugimoto, 1985). Animals with deficits in response inhibition have difficulty shifting responses on reversal tasks, continue responding when rewards are no longer presented, and fail to suppress responding on "no go" trials. Research on alcohol and aggression in humans and animals has focused on whether alcohol consumption increases violent/ aggressive behavior toward family members, peers, or rivals (see Miczek, et al., 1993 for review). However, whether a history of antisocial personality or aggressive behavior predisposes a person to excessive alcohol consumption has received little study. Measures of aggressive behavior in rodents that might reflect aspects of human antisocial behavior include social interaction/social conflict paradigms, such as isolation-induced aggression between male pairs, resident-intruder encounters, and possibly frustration-induced aggression (omission of reward) (Cairns, et al., 1983; Miczek, et al., 1993; Brain, et al., 1993). Measures of other traits potentially serving as markers of human alcoholism, such as anxiety, emotionality, activity level, and novelty-seeking, could be applied to rodents. Novelty or "sensation- seeking" can be measured by nose-poke or hole board behavior in which the animal places its nose or head into a board with equally spaced holes. Activity level can easily be measured with activity wheels or by the number of boxes crossed in an open field. Hole board behavior and exploratory open field activity, along with number of defecations and rearings in the open field, have also been used to quantitate levels of anxiety and emotionality. Other experimental paradigms for measuring anxiety include conflict paradigms, acoustic startle response, and elevated plus-maze (see Crawley, 1985; Shepard, 1986; Heilig, et al., 1994; Stout and Weiss, 1994 for reviews of all of these paradigms). A further related behavior is stress reactivity, which could be measured by responses to various stressors (social stress, isolation, early weaning), such as changes in vocalization pattern, disruption of circadian rhythms, or autonomic responses such as changes in blood pressure or heart rate (see Pohorecky, 1990; Brown, et al., 1991 for reviews). Acute behavioral tolerance to a single challenge dose of alcohol can be demonstrated in animals by comparing the extent of functional impairment at a given blood alcohol concentration on the ascending limb of the blood alcohol curve with the extent of impairment when the same alcohol concentration is reached on the descending limb. The development of acute tolerance within a single session to alcohol's effects such as motor impairment, hypothermia, and operant responding has been shown by several studies (LeBlanc, et al., 1975; Crabbe, et al., 1994b; Le, et al., 1992; Hiltunen and Jarbe, 1992). Finally, because frequency and amount of alcohol consumed are significant discriminators of alcoholic subtypes (Babor, et al., 1992; Morley and Skinner, 1986), measures of temporal patterns of alcohol consumption in rodents may be informative behavioral markers. Using operant techniques, distinctive temporal patterns of alcohol consumption have been demonstrated in the selectively bred alcohol- preferring and -nonpreferring rats (Schwarz-Stevens, et al., 1991). Such techniques could possibly be adapted to permit QTL mapping. Methodological Considerations Most QTL mapping of behavioral traits has been done in mice because of the well-developed genetic map available for this species. However, the rat genome map is now undergoing rapid development (Yamada, et al., 1994; Serikawa et al., 1992) and has already proven suitable for QTL mapping (Lindpaintner, 1992). Because many interesting behavioral paradigms have been developed in rats to study ethanol related behaviors, NIAAA encourages investigators studying rat behavior to respond to this RFA. While the choice of animal strains for study is an important feature of experimental design, applicants are encouraged to consider using any of a wide variety of strains, rather than confining their attention only to those already used extensively in alcohol research. Applicants are also encouraged to consider using existing batteries of recombinant inbred (RI) and recombinant congenic (RC) strains. Applicants are encouraged (when cost and experimental considerations permit) to test more than one behavioral paradigm on the same group of animals. Applicants may also wish to consider neurochemical measurements (e.g., receptor binding studies, in situ hybridi