Decreased Protein Degradation in Aging

这一提议的重点是伴侣介导的自噬(CMA)，这是一种分解代谢途径，介导 溶酶体中胞质蛋白的选择性降解。CMA有助于维护细胞 通过参与细胞质量控制实现动态平衡。我们之前已经发现CMA活性降低 随着年龄的增长和老年啮齿动物肝脏中适当的CMA活性的恢复，可以防止器官退化和 保护器官功能。我们认为，CMA的失效是导致CMA功能衰退的原因 并加重与年龄有关的疾病的病程。 这项建议的总体目标是1)找出CMA随年龄增长而功能衰竭的原因， 2)了解不同器官中CMA活性随年龄增长而下降的后果；3) 探索基因操作的替代干预措施，以增强衰老生物体中CMA的活性。 为此，我们打算在下一期资金中：1)确定溶酶体的贡献 底物蛋白通过CMA内化溶酶体的伴侣和辅助伴侣 转位复合体；2)阐明CMA在调节细胞脂代谢中的作用 通过维持内质网和脂滴的动态平衡和3)分析系统和 CMA活性随年龄下降的器官特异性后果与这一功能有关 在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功能衰退如何导致衰老，并可能有助于 寻找新的方法来纠正老生物体中有缺陷的CMA并防止细胞的改变 衰老的器官动态平衡特征 为此，请提供《促进健康相关研究多样性的研究补充资料》(行政助理)。 家长资助一名少数族裔博士后。

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.