Identifying regulators of APP gamma secretase

鉴定 APP γ 分泌酶的调节因子

• 批准号: 7122491
• 负责人: MING GUO
• 金额: $ 34.34万
• 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/7122491
• 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）是一种大脑神经退行性疾病，也是老年痴呆症的最常见形式。导致 AD 的主要病理事件被认为是淀粉样蛋白斑块的积累，该蛋白斑块主要由一种称为淀粉样蛋白 β 肽 (A-β) 的有毒肽在大脑中累积。 A-β 是通过两种蛋白酶（其中一种是伽马分泌酶）的作用通过蛋白水解加工从 APP 衍生而来的。 γ 分泌酶功能的异常作用是最常见的早发性家族性 AD 的基础。 γ 分泌酶存在于一个大型多蛋白复合物中，具有四种基本成分：早老素、尼卡斯特林、aph-1 和 pen-2。确定调节 γ 分泌酶活性的机制应该可以加深对 AD 发病机制的了解，并可能为开发新的诊断工具和治疗靶点提供见解。 果蝇作为分子遗传学工具已被成功地用于识别新基因和研究重要的生物过程。在果蝇中，γ分泌酶活性及其四个基本成分在功能上是保守的。因此，在果蝇中鉴定的γ分泌酶调节因子可能在功能上是保守的。我们在活的果蝇眼睛中开发了一种报告系统，使我们能够可视化γ分泌酶活性的内源水平。使用这些果蝇作为遗传背景，我们进行了遗传筛选，并确定了几个待进一步表征的候选者。该提案的具体目标是： 1. 进行功能丧失筛选，克隆候选基因并表征其功能位点。 2. 表征γ-分泌酶活性的功能获得修饰剂。 3. 确定候选基因如何与编码γ-分泌酶复合物、aph-1、pen-2、尼卡斯特林和早老素成分的基因相互作用