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)：项目摘要在过去的几年里，巨自噬与一系列神经退行性疾病有关，从聚集倾向障碍、亨廷顿病到溶酶体储存障碍、内曼-皮克C型。然而，尽管巨自噬很普遍，但人们对它的了解仍然很少，因此很难定义它是如何在发病机制中起作用的。也许并不令人惊讶的是，在不同的疾病中，巨自噬被认为是疾病进展中的一个潜在的致病因素和潜在的改善因素。如果我们要针对这种复杂的降解途径进行治疗，我们需要更好地定义自噬过程，以一种我们可以将其应用于大脑的方式。在这份拨款申请中，我们建议通过关注涉及的关键细胞器：自噬空泡(AV)来获得对宏观自噬的新见解。这种结构的形成和成熟是自噬过程的核心，目前人们对此知之甚少。使用我们开发的一种新的方法，可以分离特定的AV群体用于蛋白质组学和基于脂质的分析，我们将：1)从神经细胞和大脑鉴定AVs；2)比较和对比MAP1LC3标记的AVs和其他四种ATG8哺乳动物同源物标记的小泡的AVs；以及3)使用基于功能细胞的分析来进一步确定各种ATG8蛋白质组如何影响宏自噬。与公共卫生相关：宏自噬是一个知之甚少的过程，对于允许细胞(如神经元)去除不再起作用的蛋白质非常重要。有趣的是，这一过程被认为是许多神经退行性疾病的核心，如亨廷顿病、帕金森病、阿尔茨海默病、许多溶酶体储存疾病和其他疾病。在这里，我们建议研究宏观自噬，因为它与大脑有关，这样我们就可以利用这些信息来设计对这些许多疾病的有效治疗方法。