Chemical Genetics of a C. elegans Signaling Cascade

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Chemical genetics is an alternative to traditional genetic and biochemical strategies for studying in gene function. Chemical genetics permits screening strategies not amenable to traditional genetic methods, thereby facilitating discovery of new components of biological pathways. Small molecule compounds that bind to a specific protein can, like genetic mutations, either inhibit or activate the function of that protein. In contrast to most genetic mutations, bioactive small molecules are intrinsically conditional. In addition, chemical genetics can identify chemical intervention points within biological pathways and potential drug leads specific to these targets. The experiments described in this proposal will test a chemical genetic strategy for identifying genes involved in the three signaling pathways, TGF-beta, cyclic nucleotide, and insulin signaling, involved in the switch between growth and diapause (dauer) during Caenorhabditis elegans larval development. The specific aims of this proposal are: 1) to develop a sensitive high- throughput automated assay to measure C. elegans dauer recovery and 2) to perform a pilot screen using 1400 FDA-approved compounds. The long-term goals are to identify a collection of bioactive compounds and their molecular entry points into the TGF-beta, cyclic nucleotide, and insulin-signaling pathways in C. elegans, and to develop therapeutics against homologous targets involved in human disease. PROPOSED COMMERCIAL APPLICATIONS: Bioactive compounds directed against components of the TGF-beta, cyclic nucleotide, and insulin signaling pathways can be developed as human disease therapeutics. The C. elegans-based chemical genetic approach described herein can be genetically modified to identify compounds specific for other disease gene pathways for which there are C. elegans homologs.