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Regulation of y-secretase activity by modulatory proteins

调节蛋白对 γ 分泌酶活性的调节

基本信息

批准号：
10365920
负责人：
YUEMING LI
金额：
$ 85.44万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10365920
关键词：
Abeta synthesis Active Sites Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Behavior Binding Brain Cardiovascular Diseases Catalytic Domain Cells Cerebrovascular Disorders Complex Data Disease Down Syndrome Early Onset Alzheimer Disease Genetic Transcription Genetic study Goals HIF1A gene Hypoxia Hypoxia Inducible Factor Investigation Knock-out Knockout Mice Late Onset Alzheimer Disease Lead Link Macromolecular Complexes Maps Mediating Molecular Molecular Mechanisms of Action Mus Mutation Names Neurons Outcome Pathogenesis Pathologic Peptide Hydrolases Peptides Physiological Play Proteins Recombinants Regulation Research Role Specificity Structure Therapeutic Variant amyloid precursor protein processing cardiovascular disorder risk early onset effective therapy environmental change gain of function gamma secretase genetic regulatory protein in vivo insight loss of function mouse model nicastrin protein novel presenilin-1 presenilin-2 reconstitution response secretase trafficking transcription factor translational potential

项目摘要

Mutations in presenilin-1 (PS1) or Presenilin-2 (PS-2), the catalytic subunit of γ-secretase, lead to the early- onset form of Alzheimer’s disease (EOAD). However, the causes of late-onset AD (LOAD) are under active investigation. The pathological features and functional connectivity of both forms of AD are similar, suggesting that γ-secretase may play a causative role in the late-onset form of AD. Moreover, the pathological role of γ- secretase in EOAD has not been fully elucidated. Only a small fraction of the γ-secretase complex is catalytically active and the function and activation of the inactive complex is unknown. The objectives of this proposal are to elucidate the mechanism of action of γ-secretase modulatory proteins (GSMPs) in the regulation of γ-secretase and examine their function in AD. Here we propose to investigate how γ-secretase activity is activated by cerebrovascular disease mediated hypoxia and γ-secretase activating protein (GSAP). We will elucidate the molecular basis of GSAP in modulation of γ-secretase for the processing of APP and Notch1. We will determine the underlying mechanism by which Hif1α activates γ-secretase. Lastly, we will investigate the mechanisms by which GSAP- and Hif1α- regulate γ-secretase activity in AD mouse models. The long-term goals of this proposal are to elucidate the mechanism of γ-secretase modulation and identify novel γ-secretase regulatory proteins as well as assess their relevance to AD. Our studies focus on the molecular basis of γ-secretase modulation by modulatory proteins and have potentially significant impacts on understanding the disease mechanism and developing therapeutics.

Presenilin-1 (PS1) 或 Presenilin-2 (PS-2)（γ-分泌酶的催化亚基）的突变会导致早期- 阿尔茨海默病（EOAD）的发作形式。然而，迟发性 AD (LOAD) 的病因尚不清楚。调查。两种形式 AD 的病理特征和功能连接相似，表明 γ-分泌酶可能在迟发性 AD 中发挥致病作用。此外，γ-的病理作用 EOAD 中的分泌酶尚未完全阐明。只有一小部分 γ-分泌酶复合物具有催化作用活性复合物的功能和活性未知。该提案的目标是阐明 γ-分泌酶调节蛋白 (GSMP) 在调节 γ-分泌酶中的作用机制并检查它们在 AD 中的功能。在这里，我们建议研究γ-分泌酶活性是如何被激活的脑血管疾病介导缺氧和γ-分泌酶激活蛋白（GSAP）。我们将阐明 GSAP 调节 γ-分泌酶以加工 APP 和 Notch1 的分子基础。我们将确定 Hif1α 激活 γ 分泌酶的潜在机制。最后，我们将通过以下方式研究其机制：其中 GSAP- 和 Hif1α- 调节 AD 小鼠模型中的 γ-分泌酶活性。本提案的长期目标旨在阐明 γ-分泌酶调节机制并鉴定新型 γ-分泌酶调节蛋白并评估它们与 AD 的相关性。我们的研究重点是通过以下方式调节 γ-分泌酶的分子基础：调节蛋白，对理解疾病机制和具有潜在的重大影响开发治疗方法。