NIAAA Program Announcement

Kathy Matthews matthewk at fly.bio.indiana.edu
Fri Jul 16 12:54:45 EST 1993


I am posting this message for Robert Karp. 

The following is an excerpt from from a National Institute on Alcohol 
Abuse and Alcoholism Program Announcement of particular relevance to
Drosophilists. For the complete announcement see the Program Announcement,
Genetic Studies in Alcohol Research (PA 93-086). Copies of this and other
Program Announcements can be obtained from the National Clearinghouse on
Alcohol and Drug Information (NCADI), P.O. Box 2345, Rockville, MD 20852,
telephone:  1-800-729-6686.

         Information on research grants can be obtained from:

              Robert W. Karp, Ph.D.
              Director, Genetics Program
              Division of Basic Research
              National Institute on Alcohol Abuse and Alcoholism
              5600 Fishers Lane, Room 16C-05
              Rockville, MD 20857

              RKARP at AOAA1.SSW.DHHS.GOV
  


                 ALCOHOL-RELATED GENETIC STUDIES IN INVERTEBRATES

         Because  of  their  small  size,  short  generation time, and high
         fecundity,  the  fruit  fly  Drosophila  melanogaster and the soil
         nematode  Caenorhabditis  elegans  lend  themselves to large-scale
         systematic searches of tens to hundreds of thousands of individuals
         to  find  single-gene mutations conferring a specific phenotype of
         interest.    For  both of these invertebrate species sophisticated
         genetic  and  molecular methods are available which facilitate the
         cloning of genes based either on the phenotypes they confer, or on
         their known map locations (Ashburner, 1989; Herman and Shaw, 1987;
         Mello, et al., 1991; Coulson, et al., 1991).  The combined power of
         these   methods   has   led  to  important  contributions  to  our
         understanding of development and functioning of the nervous systems
         of   these   species.      Many   of   their  genes  critical  for
         neurotransmission  and  central  nervous system development (e.g.,
         those encoding neurotransmitter biosynthetic enzymes and receptors,
         protein kinases, adenyl cyclases, G proteins, ion channel subunits,
         cell  adhesion  proteins,  transcription  factors) have homologues
         which function critically in the vertebrate central nervous system
         as well (Molecular Neurobiology of Drosophila:  Cold Spring Harbor
         Laboratory meeting abstracts, 1991; Chalfie and White, 1988).

         In  both of these species, single-gene mutants have been described
         which  alter  sensitivity  to  volatile anaesthetics (Krishnan and
         Nash,  1990;  Sedensky  and Morgan, 1991).  Cloning of the mutated
         genes from these mutants will serve to identify gene products which
         participate  in  the  physiology  of anaesthetic sensitivity.  The
         cloned  genes  can  also  be  used to isolate mammalian (including
         human)  homologues  which  will  be  invaluable  for  studying the
         mechanisms of action of anaesthetics in these higher species.  This
         approach may well reveal targets for the action of anaesthetics not
         yet disclosed by direct genetic or biochemical studies on mammals.
         Although an approach based on systematic mutant searches of mammals
         (e.g., mice) would certainly be desirable, the impracticability of
         rearing a sufficiently large number of individuals renders studies
         in   invertebrates  more  expedient.    The  example  of  volatile
         anaesthetics  demonstrates  how  an approach based on invertebrate
         genetic  studies  provides an otherwise inaccessible entree to the
         elucidation  of  the  mechanism of action in vertebrates of a drug
         whose molecular targets have not yet been definitively identified.

         It  would  be  of  great  interest  to  characterize in detail the
         behavioral   and   developmental   responses   of  Drosophila  and
         Caenorhabditis  to  ethanol.   If such responses as attraction to,
         consumption  of, sensitivity to, tolerance to, and withdrawal from
         ethanol,  as  well as ethanol-induced developmental defects can be
         demonstrated,  then  systematic searches for single-gene mutations
         affecting these responses can greatly facilitate the elucidation of
         the entire chain of physiological events mediating these responses.
         Cloning  of  the  mutant  invertebrate  genes  discovered by these
         searches  could then lead to cloning of homologous mammalian genes
         with important functions in responses to ethanol.

         It  is difficult to predict in advance which (if any) invertebrate
         ethanol-related behaviors will prove relevant to human alcoholism.
         An  objective  test  for true homology (based on shared underlying
         genetic  or  physiological  mechanisms),  as  opposed  to  analogy
         (superficial  behavioral  similarity),  is therefore essential for
         guiding  this  line  of research.  Such a test can be accomplished
         post hoc by testing human homologues of the invertebrate genes for
         linkage to alcoholism in human pedigrees.

         Areas needing further research include:

              Characterization of behavioral and developmental responses of
              Drosophila  and    Caenorhabditis  to  ethanol.    Behavioral
              responses can include attraction to, consumption of, sedation
              by,  motor  impairment  by, tolerance to, and withdrawal from
              ethanol.

              Systematic   searches   (using   either   mutagens   or  wild
              populations)  for  mutants altered in the responses mentioned
              above.

              Mapping and cloning of the genes altered in mutants discovered
              in these screens.

              Characterization of the products of the cloned genes.

              Cloning  of  mammalian  (including  human)  homologues of the
              cloned invertebrate genes.

              Testing  for linkage of the human homologues to alcoholism in
              human pedigrees.

                                    References
                                    __________

         Ashburner  MA:    Drosophila:  A Laboratory Handbook.  Cold Spring
         Harbor, Cold Spring Harbor Laboratory Press, 1989

         Coulson  A,  Kozono  Y,  Lutterbach  B,  Shownkeen  R,  Sulston J,
         Waterston  R:   YACs and the C. elegans genome.  Bioessays 13:413-
         417, 1991

         Herman  RK,  Shaw JE:  The transposable genetic element Tc1 in the
         nematode C. elegans.  Trends Genet 3:222-225, 1987

         Krishnan KS, Nash HA:  A genetic study of the anesthetic response:
         Mutants  of  Drosophila  melanogaster  altered  in  sensitivity to
         halothane.  Proc Nat Acad Sci USA 87:8632-8636, 1990

         Mello  CC,  Kramer  JM,  Stinchcomb  D,  Ambros V:  Efficient gene
         transfer   in   C.  elegans:    extrachromosomal  maintenance  and
         integration of transforming sequences.  EMBO J 10:3959-3970, 1991

         Molecular   Neurobiology   of  Drosophila:    Cold  Spring  Harbor
         Laboratory meeting abstracts, Sept 25-29, 1991

         Sedensky  MM,  Morgan  PG:    Genetics  of  response  to  volatile
         anesthetics  in Caenorhabditis elegans.  Ann NY Acad Sci 625: 524-
         531, 1991

         Chalfie  M,  White  J:   The nervous system, in Wood WB (ed):  The
         Nematode  Caenorhabditis elegans.  Cold Spring Harbor, Cold Spring
         Harbor Laboratory Press, 1988, pp 337-395



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