Role of autophagy and retromer genes in GLP-1/Notch signaling

项目摘要 细胞需要持续的营养和能量供应来生长，代谢， 生存，并采用专门的机制，以适应养分供应的变化。 自噬是一种重要的进化保守的降解途径， 组件被回收。自噬是响应于细胞外或细胞外基质而诱导的。 细胞内应激的信号包括有限的营养，生长因子的剥夺，ER 应激和/或病原体感染。因此，自噬必须通过信号传导来调节 将环境条件与发育进程相结合的途径。一 在确定《公约》的基本组成部分方面取得了很大进展， 自噬途径，如（ATG基因）及其生化功能，而 调节自噬的机制仍然知之甚少。我们在此建议（1） 利用C语言的强大功能。线虫遗传学研究关键蛋白质 体内自噬细胞和发育过程所需的功能，以及，（2） 将我们的分析扩展到哺乳动物细胞。我们和其他人的初步数据， 表明自噬在rab-10突变体中被不适当地激活， 如果TOR活动取决于RAB-10，则为预期。RAB-10的缺失延长了C. elegans，而rab-10突变体的寿命依赖于自噬。然而， RAB-10如何调节TOR、自噬和自噬依赖过程， 生殖系增殖或寿命，是未知的。我们将（i）确定RAB-10的作用 在营养充足的条件下，饮食调节TOR和自噬， 限制，并减少胰岛素信号传导和（ii）阐明RAB-10在两个 发育过程：生殖细胞增殖和衰老。梭elegans germline是一种 有价值的模式，以研究遗传，发展，和环境控制的细菌 细胞增殖这些研究意义重大，因为它们将推动我们的 了解自噬在发育过程中的调节机制 以及用于控制细胞增殖。它们将提供信息， 关于在发育中需要自噬的组织和蛋白质， 参与自噬途径。我们的实验室在追求这一目标方面具有独特的优势 我们的专业知识在C。elegans遗传学和自噬的研究。

PROJECT SUMMARY Cells require a continuous supply of nutrients and energy for growth, metabolism, and survival, and employ dedicated mechanisms to adjust to changes in nutrient availability. Autophagy is a key evolutionarily conserved degradation pathway, by which cellular components are recycled. Autophagy is induced in response to extracellular or intracellular stress by signals that include limited nutrients, growth factor deprivation, ER stress, and/or pathogen infection. Thus, autophagy has to be regulated by signaling pathways that integrate environmental conditions, with developmental progression. A great deal of progress has been made in identifying essential components of the autophagy pathway such as (ATG genes) and their biochemical functions, whereas the mechanisms that regulate autophagy remain poorly understood. We propose here (1) to capitalize on the powerful features of C. elegans genetics to investigate critical protein functions required for autophagy cellular and developmental processes in vivo and, (2) to extend our analysis to mammalian cells. Our preliminary data, and that of others, indicate that autophagy is inappropriately activated in rab-10 mutants, as would be expected if TOR activity depends on RAB-10. Loss of RAB-10 extends lifespan in C. elegans, and the longevity of rab-10 mutants is autophagy dependent. Yet, a mechanism for how RAB-10 regulates TOR, autophagy, and autophagy dependent processes such as germline proliferation or longevity, is not known. We will (i) define the role of RAB-10 in the regulation of TOR, and autophagy, during nutrient replete conditions, dietary restriction, and reduced insulin signaling and (ii) elucidate the role of RAB-10 in two developmental processes: germline proliferation and aging. The C. elegans germline is a valuable model to study the genetic, developmental, and environmental control of germ cell proliferation. These studies are significant because they will advance our understanding of the mechanisms by which autophagy is regulated during development of a multicellular organism, and for control of cell proliferation. They will be informative in regard to both the tissues that require autophagy in development and the proteins involved in the autophagy pathway. Our laboratory is uniquely positioned to pursue this project with our expertise in C. elegans genetics and the study of autophagy.