Regulation of Growth and Proliferation by Drosophila TOR

描述（由申请人提供）：该项目的长期目标是了解雷帕霉素靶蛋白（TOR）激酶控制细胞生长和代谢的细胞和分子机制。当前预算期的工作已经确定TOR是果蝇生长的中心调节器，并描述了调节和介导TOR功能的上游电路和下游细胞过程。一个关键的未解决的问题是，TOR调节的每个细胞过程对其作用的相对程度。本研究的目标是详细了解自噬过程如何促进tor依赖的功能。自噬是一种非选择性的降解过程，其中部分细胞质被吞没并隔离到膜结合的囊泡中，并被运送到溶酶体中进行分解和再循环。自噬是长寿命蛋白质、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鉴定出来，这些基因的同源物最近被证明在后生动物的自噬中起作用。我们实验室和其他人的研究表明，正常情况下，TOR信号传导是抑制自噬的必要和充分条件；TOR的这种功能从酵母到人类细胞都是保守的。我们已经开发了一系列新的基因试剂来诱导、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信号传导中的作用和调控。这项工作有四个目标：1)研究自噬对tor依赖性生长、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调控自噬的机制；4)筛选自噬响应TOR信号所需的新基因。TOR信号在肿瘤发生、神经变性和衰老等健康相关问题中具有广泛的影响。来自许多系统的相关和遗传数据表明，自噬有助于这些影响。通过帮助揭示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.