The prevalence and mechanism of selectivity in basal autophagy

基础自噬选择性的发生率和机制

• 批准号: 9923703
• 负责人: SINA GHAEMMAGHAMI
• 金额: $ 38.17万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923703
• 关键词: Age; Autophagocytosis; Cells; Cultured Cells; Degradation Pathway; Disease; Eukaryotic Cell; Homeostasis; Impairment; Link; Maps; Methodology; Molecular; Neurodegenerative Disorders; Organelles; Pathogenicity; Pathway interactions; Prevalence; Prion Diseases; Process; Proteins; Proteome; Proteomics; Role; experimental study; insight; novel; novel therapeutic intervention; protein aggregation; protein degradation; receptor

Summary In eukaryotic cells, the process of macroautophagy is the principal catabolic pathway for the degradation of long-lived proteins and its impairment has been linked to a number of proteostatic disorders. Although it is known that macroautophagy can selectively target specific proteins and organelles for lysosomic degradation, the molecular mechanism of this selectivity remains incompletely understood. Here, we are proposing to develop novel proteome-wide approaches to investigate the mechanism of selectivity in macroautophagy. By providing global maps of autophagic flux, we will identify subsets of proteins that rely on macroautophagy for their constitutive turnover and determine the molecular receptors required for their selective degradation. Additionally, we will globally characterize the ability of macroautophagy to selectively target proteins with age-induced damage and clear pathogenic protein aggregates that accumulate during the course of prion diseases. Together, the proposed experiments will provide insights into the mechanism of cargo selection by the autophagy pathway and establish generally applicable proteomic methodologies for quantifying autophagic flux in cultured cells. Furthermore, our studies will provide insights into the role of autophagy in mitigating the proteostatic disruptions that occur during the course of prion diseases, and may identify novel therapeutic approaches targeting these disorders.

概括 在真核细胞中，巨自噬过程是主要的分解代谢途径。 长寿命蛋白质的降解及其损伤与许多因素有关 蛋白质稳态紊乱。尽管已知巨自噬可以选择性地靶向 溶酶体降解的特定蛋白质和细胞器，其分子机制 这种选择性仍然不完全清楚。在这里，我们建议开发新颖的 全蛋白质组方法研究巨自噬的选择性机制。 通过提供自噬通量的全局图，我们将识别依赖于自噬流的蛋白质子集 巨自噬的组成性周转并确定分子受体 其选择性降解所需的。此外，我们将在全球范围内描述这种能力 巨自噬选择性地靶向具有年龄诱导损伤的蛋白质并清除 在朊病毒疾病过程中积累的致病蛋白聚集体。 总之，拟议的实验将提供对货物机制的见解 通过自噬途径进行选择并建立普遍适用的蛋白质组学 量化培养细胞中自噬通量的方法。此外，我们的研究将 深入了解自噬在减轻蛋白质抑制破坏中的作用 发生在朊病毒疾病的过程中，并可能确定新的治疗方法 针对这些疾病。