Regulation of Growth and Proliferation by Drosophila TOR

描述(申请人提供)：这个项目的长期目标是了解雷帕霉素(TOR)激酶的靶点控制细胞生长和新陈代谢的细胞和分子机制。在当前预算期间的工作已经确立了TOR作为果蝇生长的中央调节因子，并表征了调节和调节TOR功能的上游回路和下游细胞过程。1个关键的悬而未决的问题涉及TOR调控的每个细胞过程对其影响的相对程度。拟议工作的目标是详细了解自噬这一过程如何有助于TOR依赖功能。自噬是一种非选择性的降解过程，在这个过程中，部分细胞质被吞噬并隔离在膜结合的小泡中，并被运输到溶酶体进行分解和回收。自噬作为长寿命蛋白质、细胞器和大量细胞质降解的主要途径，对细胞的生长和代谢具有分解代谢作用，其分解产物是饥饿条件下生存所必需的。许多调节自噬的基因现在已经在酵母中被发现，这些基因的同源基因最近被证明在后生动物的自噬中起作用。我们实验室和其他实验室的工作表明，在正常情况下，TOR信号对于抑制自噬是必要的和充分的；从酵母到人类细胞，TOR的这一功能是保守的。我们已经开发了一系列新的遗传试剂来诱导、阻断或监测果蝇的自噬。利用这些试剂，我们建议阐明自噬在响应TOR信号时的作用和调节。这项工作有4个目的：1)研究自噬对TOR依赖的生长、增殖和存活的贡献；2)分析自噬影响细胞生长的潜在机制；3)分析TOR调节自噬的机制；4)筛选响应TOR信号的自噬所需的新基因。Tor信号对肿瘤发生、神经变性和衰老等与健康相关的问题有广泛的影响。来自许多系统的相关和遗传数据表明，自噬有助于这些效应。通过揭示TOR、AOS对细胞生长和代谢影响的分子基础，这项工作将促进我们对这些过程的基本理解。

DESCRIPTION (provided by applicant): The long term goal of this project is to understand the cellular and molecular mechanisms by which the Target of Rapamycin (TOR) kinase controls cell growth and metabolism. Work in the current budget period has established TOR as a central regulator of growth in Drosophila, and has characterized the upstream circuitry and downstream cellular processes that regulate and mediate TOR function. 1 critical unresolved question concerns the relative degree to which each of the cellular processes regulated by TOR contributes to its effects. The objective of the proposed work is to achieve a detailed understanding of how 1 such process, autophagy, contributes to TOR-dependent functions. Autophagy is a non-selective degradative process in which portions of cytoplasm are engulfed and sequestered into membrane-bound vesicles, and transported to the lysosome for breakdown and recycling. As the major route by which long-lived proteins, organelles and bulk cytoplasm are degraded, autophagy has a catabolic effect on cell growth and metabolism, and its breakdown products are essential for survival under conditions of starvation. Many of the genes that regulate autophagy have now been identified in yeast, and homologs of these genes have recently been shown to function in autophagy in metazoans. Work in our laboratory and others have shown that TOR signaling is necessary and sufficient to suppress autophagy under normal conditions; this function of TOR is conserved from yeast to human cells. We have developed a series of novel genetic reagents to induce, block or monitor autophagy in Drosophila. Using these reagents we propose to elucidate the role and regulation of autophagy in response to TOR signaling. The proposed work has 4 aims: 1) investigation of the contributions of autophagy to TOR-dependent growth, proliferation and survival; 2) analysis of potential mechanisms by which autophagy influences cell growth; 3) analysis of mechanisms by which TOR regulates autophagy; 4) screen for novel genes required for autophagy in response to TOR signaling. TOR signaling has broad impacts on health-related issues such as tumorigenesis, neurodegeneration, and aging. Correlative and genetic data from a number of systems suggest autophagy contributes to these effects. By helping to reveal the molecular basis of TOR,Aos effects on cell growth and metabolism, this work will advance our basic understanding of these processes.