Chemical Genetics of a C. elegans Signaling Cascade

线虫信号级联的化学遗传学

• 批准号: 6443653
• 负责人: ANN E SLUDER
• 金额: $ 9.99万
• 依托单位: CAMBRIA BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6443653
• 关键词: Caenorhabditis elegans; biological signal transduction; gene expression; genetic techniques; high throughput technology; insulin; nucleotides; technology /technique development; transforming growth factors

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.

化学遗传学是研究基因功能的一种替代传统的遗传和生化策略。化学遗传学允许筛选策略不适合传统的遗传方法，从而促进发现生物途径的新成分。与特定蛋白质结合的小分子化合物可以像基因突变一样，抑制或激活该蛋白质的功能。与大多数基因突变相反，生物活性小分子本质上是有条件的。此外，化学遗传学可以识别生物学途径中的化学干预点和针对这些靶点的潜在药物导向。本提案中描述的实验将测试一种化学遗传策略，以识别涉及三种信号通路的基因，tgf - β，环核苷酸和胰岛素信号通路，涉及秀丽隐杆线虫幼虫发育过程中生长和滞育（daer）之间的转换。该提案的具体目标是：1)开发一种敏感的高通量自动化分析方法来测量秀丽隐杆线虫的水回收率；2)使用1400种fda批准的化合物进行试点筛选。长期目标是确定一系列生物活性化合物及其进入秀丽隐杆线虫tgf - β、环核苷酸和胰岛素信号通路的分子入口点，并开发针对人类疾病相关同源靶点的治疗方法。建议的商业应用：针对tgf - β、环核苷酸和胰岛素信号通路成分的生物活性化合物可以开发为人类疾病治疗药物。本文描述的基于秀丽隐杆线虫的化学遗传方法可以进行遗传修饰，以鉴定具有秀丽隐杆线虫同源物的其他疾病基因通路的特异性化合物。