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Mechanisms of TOR-dependent control of autophagy in Drosophila

果蝇 TOR 依赖性自噬控制机制

基本信息

批准号：
10459598
负责人：
Thomas P. Neufeld
金额：
$ 32.87万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459598
关键词：
Address Aging Animals Apoptosis Area Autophagocytosis Autophagosome Biochemical Biological Models Cell Culture Techniques Cell Death Cell Survival Cell physiology Cells Clone Cells Complement Complex Cues Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoplasm Defect Development Disease Drops Drosophila genus Equilibrium Eukaryotic Cell Event Fat Body Feedback G-Protein-Coupled Receptors Gene Family Genes Genetic Genetic Screening Goals Health Human Inflammation Insulin Receptor Knock-out Link Lysosomes Malignant Neoplasms Mammalian Cell Measurement Mediating Mediator of activation protein Membrane Methods Nerve Degeneration Nutrient Organ Culture Techniques Organelles Organism Pathway interactions Pattern Phosphorylation Physiological Physiological Processes Play Process Proteins Proton Pump Reagent Recycling Regulation Role Signal Transduction Signaling Molecule Sirolimus Source Starvation Stress System Testing Therapeutic Tissues Vesicle Work Yeasts aged base body system cancer cell experimental study extracellular fly genetic manipulation imaging approach in vivo novel nutrition protein kinase A kinase response restoration tool trafficking tumorigenesis ubiquitin-protein ligase vacuolar H+-ATPase

项目摘要

PROJECT SUMMARY The long term goal of this project is to understand the regulation and physiological roles of autophagy, a process by which proteins, organelles and bulk cytoplasm are sequestered within autophagic vesicles and delivered to the lysosome for degradation. This process plays several distinct, vital roles in the cell, acting to recycle aged or damaged components, to provide a source of nutrients in response to starvation, and in some cases to initiate cell death. These cellular functions underlie a growing appreciation for the impact of autophagy on a broad range of human illnesses and on normal physiological processes such as aging. Fundamental questions regarding autophagy remain to be addressed, including how autophagy initiation is regulated by nutrients and other signals, how autophagic vesicles mature to become competent for degradation, and how rates of autophagy are maintained at homeostatic levels optimal for cell survival. The exciting prospect of harnessing autophagy as a therapeutic tool awaits better understanding of these basic principals. The proposed studies will use genetic, biochemical and imaging-based approaches in the Drosophila system to help define mechanisms of autophagy regulation in the context of in an intact organism. Our previous studies identified a number of key targets and mechanisms through which the Target of Rapamycin (TOR) pathway inhibits autophagy in response to favorable nutrient conditions. The current proposal seeks to understand 1) how TOR signaling is integrated with other nutrient and developmental cues such as cAMP- dependent protein kinase A to control the initial steps of autophagy induction; 2) to test hypotheses that describe potential mechanisms by which TOR signaling controls the fusion of autophagosomes with lysosomes and the subsequent acidification of the autolysosome; and 3) to decipher the feedback mechanisms that provide homeostatic control limiting the rates and levels of autophagic activity. Experiments in this proposal were selected for their likelihood of having a high impact on key questions important to the field of autophagy. This proposal makes use of recently developed reagents including knockouts of several autophagy-related (Atg) genes, in vivo markers of autophagic activity, and novel methods of genetic manipulation in cell clones. Information gained from studies of autophagy in Drosophila will provide an important whole-animal complement to mammalian cell culture-based studies.

项目总结