The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Research Grants 2000-2001

Screening and Identification of Genes for Drugs in Drosophila Melanogaster

German Torres, PhD
State University of New York, Buffalo, New York

Human disease gene identification is increasing at an exceptional rate. Many genes are now thought to contribute to a variety of biochemical and behavioral deficits. Thus, characterization of a locus that controls sensitivity, for instance, to clinically relevant concentrations of cocaine and ethanol should take us from DNA sequence to biological and behavioral function. This progression, which will only be obtainable in model organisms, should significantly enhance our ability to unravel the normal function of genes or the mechanisms by which disruptions in these (same) genes result in specific disease pathologies. Recent studies give strong indications that Drosophila will be a key player for studying gene mechanisms underlying human disorders. Briefly, Drosophila melanogaster contains approximately 12,000 genes with a genome size of 165 Mb. Of these, the majority of DNA sequences have some similarity or motif to mammalian sequences. Thus, many fly genes have significant human homologs. Among the best matches are the human genes that code for DA, 5-HT, GABA, cAMP and other protein molecules mediating the actions of cocaine and ethanol.

One of the classical advantages of using fruit flies has been the extreme ease of making and identifying mutants. Further, other genetic manipulations in flies (e.g., P-element mediated germ-line transformations) are easy and cheap and thus information about human diseases learned from studying their fly homologs comes at an excellent price. In addition, the entire Drosophila genome has been sequenced; this elevates Drosophila further as a major eukaryotic model organism for studying functions of genes identified in human neuropathologies. Against these outstanding experimental features, we propose to use Drosophila as a model system for:

  1. screening and identifying gene-encoding proteins whose expression in brain are induced by cocaine and ethanol; and
  2. studying heritable genetic variance that underlies individual differences in sensitivity to cocaine and ethanol.