Role of ABeta-Degrading Proteases in Alzheimer's Disease

Aβ 降解蛋白酶在阿尔茨海默病中的作用

• 批准号: 6670137
• 负责人: WESLEY FARRIS
• 金额: $ 17.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6670137
• 关键词: Alzheimer's disease; amyloid proteins; biotransformation; disease /disorder model; endopeptidases; enzyme activity; enzyme linked immunosorbent assay; gene deletion mutation; genetic polymorphism; genetically modified animals; immunocytochemistry; laboratory mouse; laboratory rat; neprilysin; noninsulin dependent diabetes mellitus; phenotype; polymerase chain reaction; protein degradation; protein isoforms; reporter genes

DESCRIPTION (provided by applicant): Although an impressive number of studies support a central role for amyloid beta-protein (A beta) in the pathogenesis of Alzheimer's disease (AD), in the vast majority of cases, the underlying causes for the peptide's accumulation are unknown. Overproduction of A beta has been implicated in only a few cases (<5%), and newly generated AB is rapidly cleared from the brain, suggesting that A beta-degrading proteases could play a vital role in regulating cerebral levels of the peptide. Although much work has focused on the generation of A beta, relatively little is known about A beta proteolysis, which could be equally or even more important in the pathogenesis and/or potential treatments of AD. The two best-studied A beta-degrading proteases are neprilysin (NEP) and insulin-degrading enzyme (IDE). There is human genetic evidence showing linkage of the IDE region of chromosome 10q to both AD and type 2 diabetes mellitus (DM2) in some populations, which is intriguing in light of the growing evidence that DM2 and hyperinsulinemia are associated with an increased risk of developing AD. The central hypothesis of this proposal is that IDE and NEP are important regulators of A beta levels in vivo and defects in these proteases may underlie some cases of AD. My Aims are to: 1) Determine whether dysfunction of IDE leads to decreased A beta and insulin catabolism in vivo using two animal models, 2) Assess the relative roles in vivo of IDE and NEP in the metabolism of the human isoform of A beta by breeding gene-deleted mice to human APP transgenic mice, 3) Determine the biological significance of the known polymorphisms in the 5' un-translated region (UTR) of the IDE gene in AD families with allelic association to this region of chromosome 10q by quantifying transcripts and using reporter constructs and 4) Examine several aspects of the normal cell biology of IDE, such as a possible GPI-anchor, isoforms in the CSF and serum, and search for natural binding partners. The goal of this K08 proposal is to obtain the necessary scientific training in cell and molecular biology, animal breeding strategies, and statistical analysis to allow the candidate to test the above hypothesis as outlined, and in doing so, allow the candidate to develop into a successful and independent physician-scientist with the skills to help individuals with neurodegenerative dementias. The candidate's career development plan, world-class training environment, and commitment from his Department will allow the realization of this goal.

描述（由申请人提供）：尽管大多数研究都支持淀粉样蛋白β-蛋白质（A Beta）在阿尔茨海默氏病（AD）中的核心作用，但在绝大多数情况下，肽积累的基本原因是未知的。 Beta的过量生产仅与少数病例有关（<5％），而新近产生的AB迅速从大脑中清除，这表明降解β的蛋白酶在调节肽的大脑含量中可能起着至关重要的作用。尽管很多工作集中在β的产生上，但对β蛋白水解的了解很少，这在AD的发病机理和/或潜在治疗中可能同样或更重要。降解β蛋白酶的两个最佳研究的是Neprilysin（NEP）和胰岛素降解酶（IDE）。有人类的遗传证据表明，在某些人群中，染色体10q的IDE区域与AD和2型糖尿病（DM2）之间有联系，鉴于越来越多的证据表明DM2和高胰岛素血症与增加AD的风险增加有关。该提议的中心假设是IDE和NEP是体内β水平的重要调节剂，这些蛋白酶的缺陷可能是AD的某些情况的基础。我的目的是：1）确定IDE功能障碍是否导致β和胰岛素分解代谢在体内降低，2）评估IDE和NEP在体内的相对作用在IDE的体内和NEP中的代谢中，在β型蛋白质中，在β型蛋白质中，beta的人类同种型的代谢中的beta剂量在ne of the App trymential the App Tressems中有意义，该蛋白质的质量为3）。通过量化转录物和使用报告基因构建体和4）IDE正常细胞生物学的几个方面，例如可能的GP-Cantor，可能的GPI植树，可能的GPI植物，CSF和血清中的同工型和自然结合的零件。该K08提案的目的是获得细胞和分子生物学，动物育种策略和统计分析的必要科学培训，以使候选人能够检验上述假设，并在此过程中允许候选人发展成成功且独立的医师科学家，以帮助具有神经脱发的技能，以帮助具有神经脱发的技能。候选人的职业发展计划，世界一流的培训环境以及其部门的承诺将允许实现这一目标。