CHARACTERIZATION GAMMA-SEC ACTIVITY CELL FREE SYSTEM

表征 GAMMA-SEC 活性无细胞系统

• 批准号: 6845211
• 负责人: DAVID E HOKE
• 金额: $ 4.26万
• 依托单位: UNIVERSITY OF MELBOURNE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-22 至 2005-01-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845211
• 关键词: Alzheimer' s disease; amyloid proteins; cell free system; endopeptidases; enzyme activity; presenilin

DESCRIPTION (From the applicant's abstract): The neuronal production of amyloid beta (beta) from the amyloid precursor protein (APP) appears to be a necessary and invarieant step in the progression of Alzheimer's disease (AD). Three genes have been linked to early-onset AD. These genes are presenilin 1 (PS1), presenilin 2 (PS2), and APP itself. Mutations in each of these genes lead to the elevated proteolytic processing of APP into Abeta species that aggregate more readily and form amyloid plaques. The fact that three separate genes implicate Abeta as the causative agent of Alzheimer's disease makes this an important target for theraputic intervention. One way to create therapies for AD is to block the proteases that generate Abeta. These proteases have not been unidentified but the activities that create Abeta are termed beta and gamma secretase. The role of gamma secretase is especially important in the progression of AD since this activity can produce more or less aggregating forms of Abeta. It is the aim of this proposed study to characterize the role of PS1 in gamma secretase activity, identifying the subcellular localization of gamma secretase activity, and lastly to identity the gamma secretases. This will be accomplished through biochemical manipulation of cell extracts and monitoring gamma secretase activity in an in vitro assay. The identification of the protease(s) involved in producing abeta at the gamma secretase site will drastically further knowledge of the molecular mechanisms underlying AD and improve chances of creating theraputic inhibitors that slow or stop the progression of AD.

描述（摘自申请人的摘要）：淀粉样蛋白的神经元产生 淀粉样蛋白前体蛋白（APP）的β（beta）似乎是必要的 和阿尔茨海默氏病（AD）进展的不变性。三个基因 与早发广告有关。这些基因是Presenilin 1（PS1）， Presenilin 2（PS2）和应用本身。这些基因的突变导致 APP的蛋白水解处理升高到汇总的Abeta物种中 更容易形成淀粉样斑块。三个单独基因的事实 将Abeta视为阿尔茨海默氏病的致病药物，使这成为 治疗干预的重要目标。创建疗法的一种方法 AD将阻止产生Abeta的蛋白酶。这些蛋白酶不是 身份不明，但创建Abeta的活动被称为Beta和Gamma 分泌酶。伽马泌尿酶的作用在 AD的进展，因为此活动可能会产生或多或少的聚集 Abeta的形式。这项拟议的研究的目的是表征角色 伽马神分泌活性中的PS1，确定的亚细胞定位 伽马分泌酶的活动，最后是伽马分泌的身份。这 将通过对细胞提取物的生化操纵和 监测体外测定中的γ泌尿酶活性。识别 在伽玛泌尿力酶产生Abeta涉及的蛋白酶将 大量了解AD和的分子机制和 提高创造速度减慢或阻止治疗抑制剂的机会 AD的进展。