Inositol signaling in C. elegans Senescence and Diapause

描述（由申请人提供）：胰岛素样信号通路是C.优雅该通路在介导代谢和衰老中的功能在C.线虫、果蝇和哺乳动物。由于胰岛素信号通路中有如此多的保守性，我们在C。秀丽隐杆线虫将与哺乳动物胰岛素信号传导和寿命控制具有广泛的相关性。遗传分析表明，C. elegans继续鉴定可能揭示人类胰岛素样信号传导变异的途径的组分，对糖尿病具有医学意义，并了解胰岛素是如何通过 信号传导和类似的激素途径将实足年龄与许多迟发性疾病结合起来。使用RNAi筛选daf-2途径介导的长寿调节中的缺陷，我们确定了对低daf-2胰岛素/IGF 1信号传导的长寿反应所必需的综合遗传网络（9）。同样，我们对Aim 2中胰岛素信号传导组分的蛋白质组学分析已经确定了其他新的和未研究的候选基因在胰岛素信号传导中起作用。RNAi筛选和蛋白质组学在C. elegans是合适的，原因有二：第一，在过去的十年中，胰岛素信号是代谢控制的关键的组织发生了巨大的变化。胰岛素信号的研究不再仅仅局限于肝脏、肌肉甚至胰腺。胰岛素信号传导的神经和脂肪中心已经出现（7）。我们已经从整个动物提取物中鉴定出胰岛素信号的新蛋白质成分，我们的RNAi筛选是在整个动物中进行的，因此可以调查跨组织的胰岛素信号。这与哺乳动物胰岛素信号传导功能基因组学不同，哺乳动物胰岛素信号传导功能基因组学可以在组织培养中测定胰岛素反应，但不能在整个生物体的生理背景下测定。衰老和糖尿病可能更多的是生理和内分泌，不容易在细胞培养中建模。这样，C. elegans胰岛素信号遗传系统是研究人类衰老和人类糖尿病的较好模型系统。 我们对寿命调节过程的全基因组筛选也揭示了寿命调节的第二个最有效的轴调查细胞的核心组成部分，核糖体，核糖体，细胞骨架，如果检测到缺陷，则该途径耦合到与胰岛素样途径不同的寿命控制内分泌系统。我们的内分泌系统的监测和核心细胞成分的缺陷信号的探索有望照亮真核生物寿命调节的一个全新的轴。这两种内分泌系统的变化可能是人类寿命变化以及新陈代谢和药物敏感性变化的基础。

DESCRIPTION (provided by applicant): An insulin-like signaling pathway is the most potent regulator of lifespan in C. elegans. The function of this pathway in mediating metabolism and aging is conserved in C. elegans, Drosophila, and mammals. Because so much of the insulin signaling pathway is conserved, the new components we discover in C. elegans will have broad relevance to mammalian insulin signaling and longevity control. Genetic analysis in C. elegans continues to identify components of the pathway that are likely to reveal human variation in insulin-like signaling, with medical significance for diabetes and the understanding of how insulin signaling and analogous hormonal pathways couple chronological age to many late onset diseases. Using RNAi to screen for defects in daf-2 pathway mediated longevity regulation, we identified a comprehensive genetic network necessary for the longevity response to low daf-2 insulin/IGF1 signaling (9). Similarly, our proteomic analysis of insulin signaling components in Aim 2 has identified other new and unstudied candidate genes to act in insulin signaling. The use of RNAi screens and proteomics in C. elegans is opportune for two reasons: first, the tissues where insulin signaling is key for metabolic control has changed dramatically over the past decade. No longer is an exploration of insulin signaling only in the liver or muscle or even pancreas definitive. Neural and adipose centers of insulin signaling have emerged (7). We have identified new protein components of insulin signaling from whole animal extracts, and our RNAi screens are done in the whole animal, so insulin signaling across tissues is surveyed. This is unlike mammalian insulin signaling functional genomics which may assay for insulin responses in tissue culture, but not in the physiological context of a whole organism. Aging and diabetes may be more physiological and endocrine, not easily modeled in cell culture. In this way, the C. elegans insulin signaling genetic system is better model system for human aging and human diabetes than human cell culture. Our full genome screens for lifespan regulatory processes have also revealed that the second most potent axis of longevity regulation surveys core components of cells, the ribosome, the mitochondrion, the cytoskeleton, and if deficits are detected, the pathway couples to an endocrine system of longevity control that is distinct from the insulin-like pathway. Our exploration of the endocrine system for surveillance and signaling of deficits in core cellular components promises to illuminate an entirely new axis of eukaryotic lifespan regulation. Variation in both these endocrine systems may underlie human lifespan variation as well as variation in metabolism and drug sensitivities.