Decreased Protein Degradation in Aging

衰老过程中蛋白质降解减少

• 批准号: 10393546
• 负责人: ANA MARIA CUERVO
• 金额: $ 44.58万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393546
• 关键词: Age; Aging; Area; Autophagocytosis; Biology of Aging; Cellular biology; Characteristics; Complex; Custom; Defect; Deterioration; Disease; Endoplasmic Reticulum; Environment; Equilibrium; Failure; Fellowship; Funding; Future; Goals; Health; Homeostasis; Impairment; International; Intervention; Journals; Laboratories; Lipids; Liver; Lysosomes; Maintenance; Manuscripts; Mediating; Medical; Mentors; Metabolic; Metabolic Diseases; Minority; Molecular Chaperones; Muscle Weakness; Nerve Degeneration; Organ; Organ Preservation; Organism; Pathway interactions; Postdoctoral Fellow; Preparation; Process; Proteins; Quality Control; Reading; Regulation; Research; Rodent; Severities; Study models; System; Training; Training Programs; Translating; Work; Writing; age related; aged; anti aging; base; career; cell growth regulation; design; experimental study; functional decline; genetic manipulation; improved; lipid metabolism; meetings; novel strategies; parent grant; post-doctoral training; prevent; protein degradation; restoration; skills; therapy design; therapy development

This proposal focuses on chaperone-mediated autophagy (CMA), a catabolic pathway that mediates the selective degradation of cytosolic proteins in lysosomes. CMA contributes to the maintenance of cellular homeostasis by participating in cellular quality control. We have previously found that CMA activity decreases with age and that restoration of proper CMA activity in livers of old rodents prevents organ deterioration and preserves organ function. We propose that failure of CMA contributes to the functional decline characteristic of old organisms and aggravates the course of age-related diseases. The overall goal of this proposal is 1) to identify the causes behind the functional failure of CMA with age, 2) to understand the consequences of the decrease in CMA activity with age in different organs and 3) to explore alternative interventions to the genetic manipulation to enhance CMA activity in aging organisms. With this purpose, during the next period of funding we intend to: 1) determine the contribution of lysosomal chaperones and co-chaperones to the lysosomal internalization of substrate proteins through the CMA translocation complex; 2) elucidate the contribution of CMA to the regulation of cellular lipid metabolism through maintenance of endoplasmic reticulum and lipid droplet homeostasis and 3) analyze the systemic and organ-specific consequences of the decrease in CMA activity with age in relation to the function of this pathway in cellular quality control and in the regulation of the metabolic balance. Significance: This study will elucidate how functional decline of CMA contributes to aging and could help identifying new approaches to correct defective CMA in old organisms and prevent the alterations in cellular and organ homeostasis characteristics of aging A research Supplement to Promote Diversity in Health-Related Research (Admin Suppl) is requested for this parent grant to support a minority post-doctoral fellow.

该提案重点关注分子伴侣介导的自噬（CMA），这是一种介导 溶酶体中胞浆蛋白的选择性降解。 CMA 有助于维持细胞 通过参与细胞质量控制来保持体内平衡。我们之前发现CMA活性降低 随着年龄的增长，老年啮齿动物肝脏中适当的 CMA 活性的恢复可以防止器官退化， 保留器官功能。我们认为 CMA 的失败导致了功能衰退特征 衰老的有机体并加剧与年龄相关的疾病的进程。 该提案的总体目标是 1) 确定 CMA 随着年龄的增长而出现功能衰竭的原因， 2) 了解不同器官中 CMA 活性随年龄增长而降低的后果，以及 3) 探索基因操作的替代干预措施，以增强衰老生物体的 CMA 活性。 为此，在下一个资助期间，我们打算：1）确定溶酶体的贡献 分子伴侣和共分子伴侣通过 CMA 实现底物蛋白的溶酶体内化 易位复合体； 2）阐明CMA对细胞脂质代谢调节的贡献 通过维持内质网和脂滴稳态，3）分析全身和 CMA 活性随着年龄的增长而下降的器官特异性后果与其功能相关 细胞质量控制和代谢平衡调节的途径。 意义：这项研究将阐明 CMA 功能衰退如何导致衰老，并可能有助于 确定新方法来纠正旧有机体中的缺陷 CMA 并防止细胞的改变 衰老和器官稳态特征 为此，需要一份促进健康相关研究多样性的研究补充材料（管理补充材料） 用于支持少数族裔博士后研究员的家长补助金。