Genetic and Molecular Basis of Longevity

描述（由申请人提供）：胰岛素信号传导途径将哺乳动物的进食和营养状态与动物大部分组织的代谢速率和模式联系起来。我们已经证明，胰岛素样信号通路调节C。优雅这让人联想到，可能与哺乳动物中热量限制导致的寿命增加有关。因此，C. elegans胰岛素信号通路可能是哺乳动物寿命决定通路的关键组成部分。已经鉴定了许多这些基因的哺乳动物直系同源物。我们已经证明，胰岛素信号在C。线虫的神经系统是长寿调节的关键。我们将确定哪些神经元是长寿控制的中心，并将使用遗传学和RNA干扰来识别从这些神经元到衰老过程中退化的靶组织的信号。我们将确定蠕虫基因的分子身份，这些基因是通过赠款中提出的广泛的遗传和基因组分析揭示的，寻找这些基因的人类同源物，并测试这些人类蛋白质是否真的可以在C中发挥作用。elegans胰岛素样信号通路，即功能同源物。除了它们在长寿控制中可能的作用外，我们已经发现的胰岛素信号基因C。elegans遗传学可能揭示哺乳动物中胰岛素信号的组成部分，这对理解和最终治疗糖尿病很重要。糖尿病是一种影响胰岛素产生或反应的常见疾病，导致破坏性的代谢失调。成人发病或II型糖尿病中胰岛素反应缺陷的分子基础尚不清楚。很明显，它至少在一定程度上是一种遗传病。同源C. elegans代谢控制途径揭示了在胰岛素样受体下游起作用的基因以及与胰岛素会聚的其他神经内分泌信号。我们已经确定的基因的产物可能是糖尿病治疗药物开发的目标。

DESCRIPTION (provided by applicant): An insulin signaling pathway couples feeding and nutritional status in mammals to the rate and mode of metabolism in most tissues of the animal. We have shown that an insulin-like signaling pathway regulates longevity and metabolism in C. elegans. This is reminiscent and may be mechanistically related to the longevity increase caused by caloric restriction in mammals. Thus the genetic components of the C. elegans insulin signaling pathway may be key components of a mammalian longevity determining pathway. Mammalian orthologs of many of these genes have been identified. We have shown that insulin signaling in the C. elegans nervous system is key to longevity regulation. We will identify which neurons are the centers of longevity control and will use genetics and RNA interference to identify signals from those neurons to the target tissues that degenerate during the aging process. We will determine the molecular identity of the worm genes revealed by the extensive genetic and genomic analysis proposed in the grant, search for human homologues of those genes, and test whether these human proteins in fact can function in the C. elegans insulin-like signaling pathway, that is, are functional homologues. In addition to their possible roles in longevity control, the insulin signaling genes we have identified by C. elegans genetics may reveal components of insulin signaling in mammals that are important for the understanding and eventual treatment of diabetes. Diabetes is a common disease that affects the production or response to insulin, causing devastating metabolic dysregulations. The molecular basis of the defective insulin response in the adult onset or type II diabetes is unknown. It is clear that it is at least in part a genetic disease. Saturation genetic analysis of the homologous C. elegans metabolic control pathway has revealed genes that act downstream of the insulin-like receptor as well as other neuroendocrine signals that converge with insulin. The products of the genes we have identified may be targets for pharmaceutical development of diabetes therapies.