Dietary restriction and proteasome-mediated protein degradation in the aging CNS

衰老中枢神经系统中的饮食限制和蛋白酶体介导的蛋白质降解

• 批准号: 7675996
• 负责人: Jeffrey Neil Keller
• 金额: $ 26.58万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675996
• 关键词: Aging; Biochemical; Biogenesis; Biological Preservation; Cells; Central Nervous System Diseases; Complex; Data; Exhibits; Functional disorder; Impairment; Longevity; Maintenance; Mammals; Mediating; Molecular; Neuraxis; Pathway interactions; Peptide Hydrolases; Proteasome Inhibition; Proteins; Proteolysis; Proteome; Proteomics; System; Testing; Tissues; age related; base; dietary restriction; multicatalytic endopeptidase complex; new therapeutic target; normal aging; oxidation; protein degradation

DESCRIPTION (provided by applicant): The proteasome is an intracellular protease that is responsible for a significant amount of intracellular proteolysis. Inhibition of the proteasome-proteolytic pathway is thought to occur as a part of normal aging in most tissues. Proteasome inhibition likely contributes to numerous age-related alterations in the proteome, and thereby promotes a variety of cell disturbances during aging, although the lack of rigorous biochemical and proteomic analysis has made such estimations largely hypothetical and theoretical. Dietary restriction (DR) increases average and maximal lifespan in mammals, and suppresses a variety of deleterious age-related alterations at both the cellular and systems level. Our data suggests that DR ameliorates age-related impairments in proteasome function within the central nervous system (CNS). The focus of this proposal is to test the hypothesis that DR ameliorates age-related impairments in proteasome function in the CNS, as the result of direct effects on the proteasome complex. Additionally, we hypothesize that this preservation of proteolysis by DR contributes to maintenance of the proteome and inhibition of cellular disturbances during aging of the CNS. The specific aims are as follows: (1) to test the hypothesis that DR alters age-related alterations in the biogenesis, composition, and oxidation of proteasome complexes in selective regions of the CNS; (2) to test the hypothesis that DR alters age-related changes in proteasome function in selective regions of the CNS; (3) to identify which proteins in the CNS exhibit decreased degradation following proteasome inhibition; (4) to test the hypothesis that DR ameliorates age-related elevations in key proteasome substrates within the CNS. Together, these data will significantly contribute to our understanding of the molecular basis for DR-induced effects in the CNS, and contribute to our understanding of how DR ameliorates age-related impairments in proteasome function in the CNS. Additionally, these data will contribute to our understanding of how proteasome inhibition promotes disruptions in the proteome, and ultimately contributes to cellular dysfunction in the CNS. Such data may not only be important to our understanding of aging in the CNS, but may identify novel therapeutic targets for aging and age-related diseases of the CNS.

描述（由申请人提供）：蛋白酶体是一种细胞内蛋白酶，负责大量的细胞内蛋白水解。蛋白酶体-蛋白水解途径的抑制被认为是大多数组织中正常衰老的一部分。蛋白酶体抑制可能导致蛋白质组中许多与年龄相关的改变，从而促进衰老过程中的各种细胞紊乱，尽管缺乏严格的生化和蛋白质组学分析使得这种估计在很大程度上是假设和理论的。饮食限制（DR）增加哺乳动物的平均和最长寿命，并抑制细胞和系统水平上的各种有害的年龄相关的变化。我们的数据表明，DR改善中枢神经系统（CNS）内蛋白酶体功能的年龄相关性损伤。本提案的重点是检验DR改善CNS中蛋白酶体功能的年龄相关损伤的假设，这是对蛋白酶体复合物直接作用的结果。此外，我们推测，这种保存的蛋白水解DR有助于维护蛋白质组和抑制细胞的干扰，在老化的中枢神经系统。具体目的如下：（1）检验DR改变CNS选择性区域中蛋白酶体复合物的生物发生、组成和氧化的年龄相关性改变的假设;（2）检验DR改变CNS选择性区域中蛋白酶体功能的年龄相关性改变的假设;（3）鉴定CNS中哪些蛋白质在蛋白酶体抑制后表现出降低的降解;（4）检验DR改善CNS内关键蛋白酶体底物的年龄相关性升高的假设。总之，这些数据将大大有助于我们了解DR诱导的CNS效应的分子基础，并有助于我们了解DR如何改善CNS中蛋白酶体功能的年龄相关性损伤。此外，这些数据将有助于我们了解蛋白酶体抑制如何促进蛋白质组的破坏，并最终导致中枢神经系统的细胞功能障碍。这些数据可能不仅对我们理解中枢神经系统的衰老很重要，而且可能为中枢神经系统的衰老和年龄相关疾病确定新的治疗靶点。