Autophagy and Neurodegeneration

自噬和神经变性

• 批准号: 8120241
• 负责人: Thomas James Melia
• 金额: $ 34.51万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120241
• 关键词: Alzheimer' s Disease; Automobile Driving; Autophagocytosis; Autophagosome; Biochemistry; Biological Assay; Brain; Cell Line; Cells; Complex; Coupled; Cryoelectron Microscopy; Degradation Pathway; Discipline; Disease; Disease Progression; Functional disorder; Goals; Grant; Health; Heart; Hela Cells; Hepatocyte; Homologous Gene; Huntington Disease; Indium; Label; Lead; Link; Lipids; Lysosomal Storage Diseases; Mammalian Cell; Membrane; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Onions; Organelles; Parkinson Disease; Pathogenesis; Pathology; Population; Prevalence; Process; Proteins; Proteome; Proteomics; Regulation; Research; Role; Structure; Therapeutic; Tissues; Transgenic Mice; Vacuole; Vesicle; Yeasts; base; brain cell; cell type; design; effective therapy; in vivo; insight; interest; novel strategies; particle; protein degradation; stable cell line

DESCRIPTION (provided by applicant): Project Summary Over the last several years, macroautophagy has been implicated in a wide array of neurodegenerative disorders from the aggregation prone disorder, Huntington's disease to the lysosomal storage disorders, Neiman-Pick Type C. Despite its prevalence however, macroautophagy is still poorly understood, making it difficult to define how it contributes towards pathogenesis. Perhaps unsurprisingly, in different disorders, macroautophagy has been considered both as a potentially causative and potentially ameliorative element in disease progression. If we are to target this complex degradative pathway for therapeutics, we need to better define the autophagic process in a means we can apply it towards the brain. In this grant submission, we propose to gain new insights into macroautophagy by focusing on the key organelle involved: the autophagic vacuole (AV). Defined as an onion-like multilamellar vesicle that is positive for the marker MAP1LC3 (a mammalian homologue of ATG8), the formation and maturation of this structure is at the heart of the autophagic process and is by far the least understood. Using a novel approach which we have developed that can isolate specific populations of AV for proteomic and lipid-based analyses, we will: 1) characterize AVs from neuronal cells and brain; 2) compare and contrast MAP1LC3- labeled AVs from vesicles labeled with the other four ATG8 mammalian homologues; and 3) use functional cell based assays to further define how the various ATG8- proteomes impact macroautophagy. PUBLIC HEALTH RELEVANCE: Macroautophagy is a poorly understood process that is important for allowing cells, such as neurons to get rid of proteins that no longer function. Interestingly, this process has been implicated to be at the heart of many neurodegenerative diseases such as Huntington's disease, Parkinson's disease, Alzheimer's disease, many lysosomal storage diseases and others. Here we propose to study macroautophagy as it pertains to the brain so that we can use this information to design effective treatment for these many diseases.

描述（由申请人提供）：在过去几年中，大型噬菌体涉及来自聚集疾病的各种神经退行性疾病。 ，大自噬细胞仍然很少了解，因此很难定义它如何促进发病机理。也许毫不奇怪，在不同的疾病中，大型噬菌体被认为是疾病进展中潜在的病因和潜在的改善元素。如果我们要针对这种复杂的降解性治疗途径，我们需要更好地定义自噬过程，以便将其应用于大脑。在此赠款提交中，我们建议通过关注所涉及的关键细胞器：自噬液泡（AV）来获得对大型噬菌体的新见解。定义为一种对标记MAP1LC3（ATG8的哺乳动物同源物）为阳性的洋葱样的多层囊泡，该结构的形成和成熟是自噬过程的核心，并且迄今为止最不理知识。使用我们开发的一种新方法，可以将基于蛋白质组学和脂质分析的AV特定种群分离出来，我们将：1）表征来自神经元细胞和大脑的AV； 2）比较和对比度MAP1LC3-与其他四个ATG8哺乳动物同源物标记的囊泡标记为AV； 3）使用基于功能细胞的测定进一步定义各种ATG8-蛋白质组如何影响大型噬菌体。公共卫生相关性：大型噬菌学是一个鲜为人知的过程，对于允许细胞（例如神经元）摆脱不再起作用的蛋白质很重要。有趣的是，这一过程被认为是许多神经退行性疾病的核心，例如亨廷顿氏病，帕金森氏病，阿尔茨海默氏病，许多溶酶体储存疾病等。在这里，我们建议研究与大脑有关的大型噬菌体，以便我们可以使用这些信息来设计有效的这些疾病。