Decreased Protein Degradation in Aging

衰老过程中蛋白质降解减少

• 批准号: 9905323
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905323
• 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.

这项建议的重点是伴侣介导的自噬（CMA），这是一种介导自噬的分解代谢途径。 溶酶体中胞质蛋白的选择性降解。CMA有助于维持细胞 通过参与细胞质量控制来维持体内平衡。我们以前发现CMA活性降低 随着年龄的增长，老年啮齿动物肝脏中适当CMA活性的恢复可防止器官退化， 保持器官功能。我们认为，CMA的失败有助于功能衰退的特点， 衰老的生物体，并延缓与年龄有关的疾病的进程。 该提案的总体目标是：1）确定CMA随年龄增长而功能失效的原因， 2)了解不同器官中CMA活性随年龄增长而降低的后果; 3） 探索基因操作的替代干预措施，以增强衰老生物体中的CMA活性。 为此，在下一个资助期内，我们打算：1）确定溶酶体的贡献， 分子伴侣和辅助分子伴侣通过CMA对底物蛋白质的溶酶体内化 阐明CMA对细胞脂质代谢的调节作用 通过维持内质网和脂滴的稳态和3）分析系统和 CMA活性随着年龄的增长而降低的器官特异性后果与这种功能有关。 在细胞质量控制和代谢平衡的调节途径。 意义：这项研究将阐明CMA的功能下降如何促进衰老， 确定新的方法来纠正旧生物体中有缺陷的CMA， 和器官的稳态特征 一个研究补充，以促进健康相关研究的多样性（行政增刊）是要求这一点 家长补助金，以支持少数民族博士后研究员。