Decreased Protein Degradation in Aging

衰老过程中蛋白质降解减少

基本信息

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
项目类别：
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

项目摘要

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.

该提案侧重于伴侣介导的自噬（CMA），这是一种介导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，体内平衡。我们以前发现CMA活性降低随着年龄的增长和恢复旧啮齿动物肝脏中CMA活动的适当活动，可防止器官恶化和保留器官功能。我们建议CMA的失败有助于功能下降的特征旧生物体加剧了与年龄有关的疾病。该提案的总体目标是1）确定CMA随着年龄的增长的功能失败的原因， 2）了解与不同器官年龄随着年龄的年龄的减少和3）的后果探索遗传操作的替代干预措施，以增强衰老生物的CMA活性。出于这个目的，在下一个资金期间，我们打算：1）确定溶酶体的贡献通过CMA，伴侣和伴侣到底物蛋白的溶酶体内在化易位配合物； 2）阐明CMA对细胞脂质代谢的调节的贡献通过维持内质网和脂质滴位稳态，3）分析系统性和与此功能有关的CMA活性下降的器官特异性后果细胞质量控制和代谢平衡调节中的途径。意义：这项研究将阐明CMA的功能下降如何促进衰老，并可以帮助确定纠正旧生物中CMA有缺陷的CMA的新方法，并防止细胞的改变和器官稳态的衰老特征为此要求促进与健康相关研究多样性的研究补充父母赠款支持少数派博士后研究员。