Identifying Regulators of APP Gamma Secretase

鉴定 APP γ 分泌酶的调节因子

• 批准号: 6620365
• 负责人: MING GUO
• 金额: $ 17.06万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620365
• 关键词: Alzheimer's disease; Drosophilidae; amyloid proteins; arthropod genetics; disease /disorder proneness /risk; endopeptidases; enzyme activity; gene mutation; genetic enhancer element; genetic mapping; genetic screening; intermolecular interaction; molecular cloning; neural degeneration; pathologic process; presenilin; reporter genes; transposon /insertion element

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder and the most common senile dementia. Three genes have been identified that mediate early onset familial AD: The amyloid precursor protein (APP), and presenilin 1 and 2. The deposition of amyloid beta peptide (Abeta) to the brain is the major pathological events leading to AD. Abeta is derived from APP by proteolytic processing via the sequential action of 2 proteases known as beta and gamma secretases. Presenilins are intimately associated with, if not they are, gamma secretase. Thus, identifying mechanisms by which gamma secretase activity and presenilins are regulated should lead to an increase in the understanding of AD pathogenesis and mechanisms of neurodegeneration. Drosophila has been used with great success as a molecular genetic tool to identify new genes and study essential biological processes. Since many genes and signaling pathways are evolutionarily conserved, human homologs of these genes may provide insights for new diagnosis and treatment. The longterm goal of this work is to use the fly to identify regulators of gamma secretase activity, and translate the findings to study the pathogenesis of human AD. The Specific Aims of this proposal are to: 1) Use a functionbased gamma secretase reporter implemented in the fly eye as a background in which to screen for regulators of gamma secretase activity, 2) clone and characterize one or more of the genes identified during these screens. 3) identify human homologs of the genes identified in the screens. Begin the process of determining if mutations in these genes might serve a diagnostic purpose for identifying individuals at altered risk of developing AD.

描述（由申请人提供）：阿尔茨海默氏病（AD）是 神经退行性疾病和最常见的老年痴呆症。三个基因 已经确定介导早期发作家族性AD：淀粉样蛋白 前体蛋白（APP）和Presenilin 1和2。淀粉样蛋白β的沉积 大脑的肽（Abeta）是导致AD的主要病理事件。 ABETA是通过蛋白水解处理通过顺序作用衍生而来的 2个被称为β和伽马分泌的蛋白酶。 presenilins是密切的 与伽马分泌酶相关的是，如果不是的话。因此，识别机制 通过调节伽马分泌酶的活性和presenilins应导致 对AD发病机理的理解和机制的理解增加了 神经变性。果蝇已作为分子成功使用了 识别新基因并研究基本生物学过程的遗传工具。 由于许多基因和信号通路在进化上是保守的，人类 这些基因的同源物可以为新的诊断和治疗提供见解。 这项工作的长期目标是利用苍蝇来确定 伽玛泌尿酶活性，并翻译发现以研究发病机理 人类广告。该提案的具体目的是：1）使用基于功能的 伽马分泌酶记者在飞眼中实施，作为背景 伽马神分泌酶活性调节剂的屏幕，2）克隆并表征 在这些筛选过程中鉴定出的一个或多个基因。 3）确定人类 筛选中鉴定的基因的同源物。开始 确定这些基因中的突变是否可能针对诊断目的 识别患有发展AD风险的人。