UBIQUITIN DEFICIENCY IN AGING AND NEURODEGENERATION

衰老和神经退行性疾病中的泛素缺乏

• 批准号: 7012800
• 负责人: RON R KOPITO
• 金额: $ 16.01万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012800
• 关键词: aging; cytoprotection; disease /disorder etiology; disease /disorder model; electron microscopy; environmental toxicology; gene expression; genetic models; genetic susceptibility; genetically modified animals; green fluorescent proteins; laboratory mouse; model design /development; neural degeneration; neurotoxins; nucleic acid sequence; physiologic stressor; polymerase chain reaction; proteasome; protein deficiency; proteolysis; southern blotting; ubiquitin

DESCRIPTION (provided by applicant): The ubiquitin proteasome system (UPS) is the principal mechanism for degrading unwanted proteins in eukaryotic cells. The UPS contributes an important role in protecting cells against stress resulting from environmental damage to proteins and against the potentially deleterious consequences of the production of error-containing polypeptides. A decline in activity of specific elements of the UPS has been reported to occur during normal aging and in the pathogenesis of many late-onset neurodegenerative diseases. Despite tantalizing genetic evidence linking neurodegenerative diseases like Parkinson's to specific lesions in components of the UPS, the role of this proteolytic system in maintaining protein homeostasis and resisting stress in intact animals has never been studied. The proposed exploratory project aims to create mouse lines that are defective in the ability to induce expression of ubiquitin, a key step in the UPS, in response to stress. Mice harboring deletions of the two polyubiquitin genes, UbB and UbC will be bred and intercrossed to produce lines containing progressively severe ubiquitin deficiencies. These ubiquitin-deficient mice will be closely monitored for life-span, as well as developmental, neurological, behavioral and growth phenotypes. The effect of ubiquitin deficiency on the sensitivity to environmental neurotoxins will be evaluated. Finally these mice will be backcrossed with C57BL/6 mice to generate congenic lines suitable for breeding with established and emerging models of aging and neurodegeneration.

描述（由申请人提供）： 泛素蛋白酶体系统（UPS）是真核细胞降解有害蛋白的主要机制。UPS在保护细胞免受由环境对蛋白质的损害引起的应激和免受含错误多肽的产生的潜在有害后果方面起重要作用。据报道，UPS的特定元素的活性下降发生在正常衰老期间和许多迟发性神经退行性疾病的发病机制中。尽管有诱人的遗传证据将神经退行性疾病如帕金森氏症与UPS组分中的特定病变联系起来，但这种蛋白水解系统在维持蛋白质稳态和抵抗完整动物应激中的作用从未被研究过。拟议的探索性项目旨在创建小鼠品系，这些小鼠品系在诱导泛素表达的能力方面存在缺陷，泛素是UPS中的关键步骤，以应对压力。将培育并杂交具有两个多聚泛素基因UbB和UbC缺失的小鼠，以产生含有进行性严重泛素缺陷的品系。将密切监测这些泛素缺陷小鼠的寿命，以及发育，神经，行为和生长表型。将评估泛素缺乏对环境神经毒素敏感性的影响。最后，这些小鼠将与C57 BL/6小鼠回交，以产生适合与已建立和新出现的衰老和神经变性模型进行育种的同类系。