CHARACTERIZATION GAMMA-SEC ACTIVITY CELL FREE SYSTEM

表征 GAMMA-SEC 活性无细胞系统

• 批准号: 6696998
• 负责人: DAVID E HOKE
• 金额: $ 0.55万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6696998
• 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(摘自申请者的摘要)：淀粉样蛋白的神经元产生 淀粉样前体蛋白(APP)的贝塔(Beta)似乎是必需的 而且在阿尔茨海默病(AD)的发展过程中是始终如一的。三个基因 与早发性阿尔茨海默病有关。这些基因是早老素1(PS1)， 早老素2(PS2)和APP本身。这些基因中的每一个突变都会导致 APP被提升的蛋白质分解加工成聚集的Abeta物种 更容易形成淀粉样斑块。事实上，三个独立的基因 将Abeta作为阿尔茨海默病的致病因素使这一点成为 治疗干预的重要靶点。一种创建治疗方法的方法 AD是为了阻止产生Abeta的蛋白酶。这些蛋白酶还没有被 未知，但产生Abeta的活动被称为Beta和Gamma 分泌酶。伽马分泌酶的作用尤其重要。 AD的进展，因为此活动可产生或多或少的聚集 Abeta的形式。这项拟议研究的目的是描述这一角色的特征 PS1在伽马分泌酶活性中的作用，确定了PS1的亚细胞定位 伽马分泌酶活性，最后鉴定伽马分泌酶。这 将通过生物化学操作细胞提取液和 在体外试验中监测伽马分泌酶活性。身份的鉴定 参与在伽马分泌酶部位产生阿贝塔的蛋白酶(S)将 对阿尔茨海默病和阿尔茨海默病分子机制的进一步认识 增加创造治疗抑制剂的机会，以减缓或阻止 AD的进展。