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: 9140412
• 负责人: SINA GHAEMMAGHAMI
• 金额: $ 36.27万
• 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/9140412
• 关键词: Age; Autophagocytosis; Cell physiology; Cells; Cultured Cells; Degradation Pathway; Disease; Eukaryotic Cell; Homeostasis; Impairment; Life; Link; Maps; Methodology; Molecular; Neurodegenerative Disorders; Organelles; Pathway interactions; Prevalence; Prion Diseases; Proteins; Proteome; Proteomics; Role; insight; novel; novel therapeutic intervention; protein aggregate; protein degradation; receptor; research study

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，大噬菌的过程是主要的分解代谢途径 长寿命蛋白及其损害的降解与许多 蛋白抑制疾病。尽管众所周知，大自自噬可以有选择地靶向 特异性蛋白质和细胞器溶酶体降解，分子机制 这种选择性仍然不完全理解。在这里，我们提议开发小说 全蛋白质组的方法研究大噬细胞中选择性的机理。 通过提供自噬通量的全球图，我们将确定依赖蛋白质的子集 大量噬菌体的组成性营业额并确定分子受体 其选择性降解所需的。此外，我们将在全球范围内表征能力 大自噬细胞的选择性靶向蛋白质，并具有年龄诱导的损害和清除 病毒疾病过程中积累的致病蛋白聚集体。 提出的实验将共同提供有关货物机制的见解 通过自噬途径进行选择，并建立通常适用的蛋白质组学 量化培养细胞中自噬通量的方法。此外，我们的研究将 提供有关自噬在减轻蛋白质抑制作用中的作用的见解 发生在prion疾病的过程中，并可能识别出新的治疗方法 针对这些疾病。