The Role of the Proteasome in Aging

蛋白酶体在衰老中的作用

• 批准号: 7690808
• 负责人: Karl A Rodriguez
• 金额: $ 5.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690808
• 关键词: Accounting; Active Sites; Affect; Age; Aging; Aging-Related Process; Apoptosis; C57BL/6 Mouse; Caloric Restriction; Cell Aging; Cell Cycle; Cells; Characteristics; Charge; Classification; Complex; Data; Disease; Electrophoresis; Enzymes; Excision; Garbage; Genetic Transcription; Goals; Learning; Life; Link; Liver; Location; Metabolic; Metabolism; Modeling; Molecular; Molecular Profiling; Mus; Oxidative Stress; Pathway interactions; Pattern; Peptide Hydrolases; Peptides; Physiological; Process; Property; Proteins; Quality Control; Role; Sampling; Services; Specificity; Testing; Time; Tissues; Ubiquitin; Western Blotting; age group; age related; base; indexing; inhibitor/antagonist; mouse model; multicatalytic endopeptidase complex; novel; oxidative damage; protein degradation

DESCRIPTION (provided by applicant): Due to its known role in protein turnover in the cell, the ubiquitin-proteasome pathway is expected to be a key player in cellular aging. The proteasome, a multifunctional, multisubunit proteolytic enzyme, is a focal point in the pathway and is in charge of controlled cleavage of short-lived metabolic regulator proteins and damaged long-lived proteins. Both the regulatory role and the "garbage removal" function may have a role in age-related metabolic slowdown and diseases. However, studies implicating the proteasome in aging have been limited, inconclusive, and at times contradictory. I propose to characterize proteasomal assemblies in aging mice liver tissue in a truly comprehensive manner: separately in distinct subcellular compartments, and taking into account activity, specificity, assembly status, and subunit composition. The emerging evidence that proteasomes perform specific duties based on subcellular location justifies my approach. I hypothesize that there is a set of age-related alternations, which collectively form a characteristic pattern of properties that constitutes a signature of aging. I wish to call such signature the proteasome aging index. My preliminary data support the notion that such index can be revealed. Specifically, I propose to: (1) define the proteasome aging index in each age group specific for subcellular localization of proteasomes. I will perform molecular profiling of the following properties of proteasome: content and composition of proteasome subassemblies, protein content of selected subunits of the subassemblies and peptidase activities of all three active sites, determined with model substrates. (2) I will correlate the proteasome index with the pattern of cleavage of natural substrates. (3) Finally, I will employ the proteasome aging index to establish the state of the proteasome pathway in the oxidative stress mice models: the SOD1-/- mice characterized by an increased oxidative stress and mice subjected to caloric restriction accepted as a model of decreased oxidative stress. Successful launching of the proteasome aging index will serve as a novel platform to pursue age-related alterations in the proteasome and its molecular context, learning about physiological consequences of the changes, and propose the means to correct them. The proteasome, a multifunctional enzyme responsible for controlled degradation of most of cellular proteins, has been linked to an age-related decline in protein turnover. I plan to define a pattern of age-related changes in the proteasome: the "proteasome index of aging". Such an index will help to detect signs of cellular aging and help to establish treatments aiming at controlling the aging processes.

描述（由申请人提供）：由于其在细胞中蛋白质周转中的已知作用，泛素 - 蛋白酶体途径有望成为细胞衰老的关键参与者。蛋白酶体是一种多功能的多功能蛋白水解酶，是途径的焦点，并且负责短暂的代谢调节蛋白的受控切割和损坏的长寿命蛋白。调节作用和“清除垃圾”功能都可能在与年龄相关的代谢放缓和疾病中起作用。但是，涉及蛋白酶体衰老的研究是有限的，没有定论的，有时甚至是矛盾的。我建议以真正的全面方式表征衰老小鼠肝组织中的蛋白酶体组件：分别在不同的亚细胞隔室中，并考虑到活动，特异性，组装状态和亚基组成。蛋白酶体基于亚细胞位置执行特定职责的新兴证据证明了我的方法是合理的。我假设存在一组与年龄相关的交替，它们统称构成构成衰老标志的特性模式。我希望将这种签名称为蛋白酶体衰老指数。我的初步数据支持可以揭示此类索引的概念。具体而言，我建议：（1）定义针对蛋白酶体亚细胞定位的每个年龄组中的蛋白酶体老化指数。我将对蛋白酶体的以下特性进行分子分析：蛋白酶体亚构造的含量和组成，由模型底物确定的所有三个活性位点的亚组件选定亚基的蛋白质含量以及所有三个活性位点的肽酶活性。 （2）我将将蛋白酶体指数与天然底物的切割模式相关联。 （3）最后，我将采用蛋白酶体衰老指数在氧化应激小鼠模型中建立蛋白酶体途径的状态：SOD1 - / - 小鼠的特征是氧化应激增加，并且接受了受热量限制的小鼠，被接受为减少氧化应激的模型。蛋白酶体衰老指数的成功启动将成为一个新的平台，以追求蛋白酶体及其分子环境中与年龄相关的变化，了解变化的生理后果，并提出纠正它们的手段。蛋白酶体是一种多功能酶，负责大多数细胞蛋白的受控降解，与蛋白质更新与年龄相关的下降有关。我计划定义蛋白酶体与年龄相关的变化模式：“衰老的蛋白酶体指数”。这样的指数将有助于检测细胞衰老的迹象，并有助于建立旨在控制衰老过程的治疗方法。