Identifying regulators of APP gamma secretase

鉴定 APP γ 分泌酶的调节因子

• 批准号: 6855778
• 负责人: MING GUO
• 金额: $ 35.11万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855778
• 关键词: Alzheimer' s disease; Drosophilidae; amyloid proteins; endopeptidases; functional /structural genomics; gene interaction; genetic screening; molecular cloning; neurogenetics; neuroregulation; presenilin; tissue /cell culture

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder of the brain and the most common form of senile dementia. The central pathological event leading to AD is thought to be the accumulation of amyloid plaques consisting primarily of a toxic peptide known as amyloid beta peptide (A-beta) in the brain. A-beta is derived from APP by proteolytic processing via the action of two proteases, one of which is gamma secretase. The aberrant action of gamma secretase function underlies the most common early onset familial AD. Gamma secretase resides in a large multi-protein complex with four essential components: presenilin, nicastrin, aph-1 and pen-2. Identifying mechanisms by which gamma secretase activity is regulated should lead to an increased understanding of AD pathogenesis and may provide insight in developing new diagnostic tools and therapeutic targets. Drosophila has been used with great success as a molecular genetic tool to identify new genes and study essential biological processes. In Drosophila, the gamma secretase activity and its four essential components are functionally conserved. Thus regulators of gamma secretase identified in Drosophila are likely to be functionally conserved. We have developed a reporter system in the living Drosophila eye that allows us to visualize the endogenous level of gamma secretase activity. Using these flies as a genetic background, we have carried out genetic screens and have identified several candidates to be characterized further. The specific aims of this proposal are: 1. Carry out loss-of-function screens, clone candidate genes and characterize their sites of function. 2. Characterize gain-of-function modifiers of gamma-secretase activity. 3. Determine how the candidate gene interacts with genes encoding components of gamma-secretase complex, aph-1, pen-2, nicastrin and presenilin

描述（由申请人提供）：阿尔茨海默氏病（AD）是大脑的神经退行性疾病，也是老年痴呆症的最常见形式。导致AD的中心病理事件被认为是主要由大脑中称为淀粉样蛋白β肽（A-BETA）组成的淀粉样蛋白斑的积累。 A-beta是通过蛋白水解处理通过两种蛋白酶的作用来得出的，其中一种是伽马泌物酶。伽马神分泌酶功能的异常作用是最常见的早期发作家族广告。 γ泌尿酶驻留在具有四个基本组成部分的大型多蛋白质复合物中：Presenilin，Nicastrin，APH-1和PEN-2。识别调节γ泌尿酶活性的机制应导致对AD发病机理的理解，并可能为开发新的诊断工具和治疗靶标提供见解。 果蝇已成功地将果蝇用作分子遗传工具，以识别新基因并研究基本的生物学过程。在果蝇中，伽马神分泌酶活性及其四个基本成分在功能上是保守的。因此，在果蝇中鉴定出的伽马神分泌酶的调节剂可能在功能上是保守的。我们已经在活的果蝇眼中开发了一个记者系统，使我们能够可视化伽马神分泌酶活性的内源水平。使用这些苍蝇作为遗传背景，我们进行了遗传筛选，并确定了几个候选者要进一步表征。该提案的具体目的是： 1。执行功能丧失屏幕，克隆候选基因并表征其功能部位。 2。表征γ-分泌酶活性的功能性修饰符。 3。确定候选基因如何与编码γ-分泌酶复合物，APH-1，PEN-2，NICASTRIN和PRESENILIN的基因相互作用