Regulation of Growth and Proliferation by Drosophila TOR

果蝇 TOR 对生长和增殖的调节

• 批准号: 7251938
• 负责人: Thomas P. Neufeld
• 金额: $ 27.97万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251938
• 关键词: Accounting; Aging; Autophagocytosis; Binding; Biochemical Genetics; Biological Assay; Budgets; Cell Cycle Regulation; Cell physiology; Cells; Condition; Cues; Cytoplasm; Data; Disruption; Drosophila genus; Energy Metabolism; Eukaryota; Eukaryotic Cell; Family; Feedback; Funding; Genes; Genetic; Genetic Screening; Genetic screening method; Goals; Growth; Growth Factor; Homologous Gene; Human; Investigation; Laboratories; Life; Longevity; Lysosomes; Mammalian Cell; Mediating; Membrane; Metabolism; Mitochondria; Modeling; Molecular; Monitor; Nerve Degeneration; Numbers; Nutrient; Oncogene Proteins; Organelles; Oxygen; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Protein Biosynthesis; Protein Dynamics; Protein Kinase; Proteins; Proteolysis; RNA; Rate; Reagent; Recycling; Regulation; Relative (related person); Research Personnel; Resistance; Role; Route; Series; Signal Transduction; Sirolimus; Starvation; Stress; System; Testing; Transcriptional Regulation; Transport Vesicles; Work; Yeasts; base; cell growth; cell type; genetic analysis; genetic manipulation; novel; programs; research study; response; tumorigenesis; uptake

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.

描述（由申请人提供）：该项目的长期目标是了解雷帕霉素（TOR）激酶靶标的细胞和分子机制控制细胞的生长和代谢。当前预算期间的工作已确立了TOR作为果蝇增长的中心调节因子，并表征了调节和介导Tor功能的上游电路和下游蜂窝过程。 1关键未解决的问题涉及由TOR调节的每个细胞过程对其效应的相对程度。拟议工作的目的是详细了解1此类过程，自噬如何有助于TOR依赖性功能。自噬是一种非选择性的降解过程，其中一部分细胞质被吞没并隔离到膜结合的囊泡中，并运输到溶酶体中以分解和回收。作为长寿命蛋白，细胞器和大块细胞质的主要途径，自噬对细胞生长和代谢具有分解代谢作用，其分解产物对于在饥饿条件下对于生存至关重要。现在已经在酵母中鉴定出调节自噬的许多基因，并且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。在我们的实验室和其他工作中的工作表明，在正常情况下，TOR信号传导是必要的，足以抑制自噬； Tor的这种功能是从酵母到人类细胞的保守。我们已经开发了一系列新型的遗传试剂来诱导，阻止或监测果蝇中的自噬。我们建议使用这些试剂阐明自噬对TOR信号的作用和调节。拟议的工作有4个目标：1）研究自噬对TOR依赖性生长，增殖和生存的贡献； 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）自噬所需的新型基因响应TOR信号传导所需的新基因。 TOR信号对与健康相关的问题产生广泛的影响，例如肿瘤发生，神经退行性变化和衰老。来自许多系统的相关和遗传数据表明自噬对这些效果有所影响。通过帮助揭示TOR的分子基础，AOS对细胞生长和代谢的影响，这项工作将提高我们对这些过程的基本理解。