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The molecular basis for the induction of autophagy

诱导自噬的分子基础

基本信息

批准号：
8535719
负责人：
Michael Joseph Ragusa
金额：
$ 5.22万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535719
关键词：
Alkaline Phosphatase Antineoplastic Agents Architecture Autophagocytosis Binding Biochemical Biological Assay Cancer Etiology Catalytic Domain Cell physiology Cells Cellular biology Complex Crystallization Diabetes Mellitus Disease Docking Drug Design Drug Targeting Drug usage Fractionation Future Genes Goals Homeostasis Human Huntington Disease Hybrids Image Immune Individual Insecta Lead Lipids Lysosomes Malignant Neoplasms Mammalian Cell Measures Mediating Modeling Molecular Molecular Conformation Molecular Sieve Chromatography Molecular Weight Monitor Multiprotein Complexes Neurodegenerative Disorders Neurons Organelles Parkinson Disease Pathway interactions Pharmacologic Substance Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Process Protein Biosynthesis Protein Dephosphorylation Protein Kinase Proteins Proteolysis Regulation Research Saccharomyces cerevisiae Sirolimus Solutions Specificity Structure Testing Validation Work X-Ray Crystallography Yeasts base design in vitro Assay in vivo inhibition of autophagy insight interest mutant novel overexpression particle protein complex protein degradation protein misfolding reconstruction research study scaffold therapeutic target tumor progression

项目摘要

DESCRIPTION (provided by applicant): Protein turnover within a cell is regulated by protein synthesis and degradation. One pathway of protein degradation is autophagy, which is capable of degrading misfolded proteins and damaged organelles. A dysregulation of autophagy has been implicated in various cancers, and neurodegenerative diseases including Parkinson's and Huntington's disease. Due to the importance of autophagy in normal cellular function and its dysregulation in disease states there has been a significantly increased interest in autophagy related research within the last 15 years. Despite the increased interest in autophagy research, very few structures of autophagy related proteins have been determined. Therefore, many of the molecular mechanisms that regulate autophagy, including the mechanism of activation of the Atg1/ULK1 complex, remain to be elucidated. The Atg1/ULK1 is the most upstream complex that regulates autophagy and upon activation serves to initiate autophagy. Inhibition of Atg1/ULK1 complex activation results in the near complete inhibition of autophagy demonstrating that the Atg1/ULK1 complex is a master regulator of autophagy. Our goal is to understand the molecular mechanisms that regulate the initiation of autophagy by the Atg1/ULK1 complex, which will provide the molecular basis for the induction of autophagy. To this end, I will perform a structural and functional characterization of the inactive and active forms of the Atg1/ULK1 complex. This work will include structure determination of the Atg1/ULK1 complex as well as a structure driven mutational analysis of the complex to validate and further investigate possible mechanisms for complex activation. Additionally, autophagy has been shown to be induced by pharmaceutical drugs that are used to slow tumor progression. As a result, this work will not only reveal the molecular mechanisms for the induction of autophagy but may also drive future drug design towards targeting the Atg1/ULK1 complex to induce autophagy with higher specificity.

描述（由申请人提供）：细胞内的蛋白质周转由蛋白质合成和降解调节。蛋白质降解的途径之一是自噬，它能够降解错误折叠的蛋白质和受损的细胞器。自噬失调与多种癌症和神经退行性疾病（包括帕金森病和亨廷顿病）有关。由于自噬在正常细胞功能中的重要性及其在疾病状态中的失调，在过去的15年中，自噬相关研究的兴趣显著增加。尽管对自噬的研究越来越感兴趣，但很少有自噬相关蛋白的结构被确定。因此，调控自噬的许多分子机制，包括Atg1/ULK1复合物的激活机制，仍有待阐明。Atg1/ULK1是调控自噬的最上游复合体，激活后可启动自噬。抑制Atg1/ULK1复合体激活导致自噬几乎完全抑制，这表明Atg1/ULK1复合体是自噬的主要调节因子。我们的目标是了解Atg1/ULK1复合物调控自噬启动的分子机制，为诱导自噬提供分子基础。为此，我将对Atg1/ULK1复合物的非活性和活性形式进行结构和功能表征。这项工作将包括Atg1/ULK1复合物的结构确定以及复合物的结构驱动突变分析，以验证和进一步研究复合物激活的可能机制。此外，自噬已被证明是由用于减缓肿瘤进展的药物诱导的。因此，这项工作不仅将揭示诱导自噬的分子机制，而且可能推动未来的药物设计朝着靶向Atg1/ULK1复合物的方向发展，以更高的特异性诱导自噬。