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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：
10064120
负责人：
YUEMING LI
金额：
$ 85.98万
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/10064120
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 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 Presenile Alzheimer Dementia 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

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.

早老素-1（PS-1）或早老素-2（PS-2）（γ-分泌酶的催化亚基）的突变导致了早期- 阿尔茨海默病（EOAD）的发病形式。然而，晚发性AD（LOAD）的病因尚不活跃，调查两种形式的AD的病理特征和功能连接相似，表明 γ-分泌酶可能在晚发型AD中起致病作用。此外，γ- EOAD中的分泌酶尚未完全阐明。只有一小部分的γ-分泌酶复合物催化活性和功能和激活的非活性复合物是未知的。本提案的目标是阐明γ-分泌酶调节蛋白（GSMPs）在γ-分泌酶调节中的作用机制并研究它们在AD中的作用。在这里，我们建议研究γ-分泌酶活性是如何被激活的，脑血管病介导的缺氧与γ-分泌酶激活蛋白（GSAP）的关系。我们将阐明 GSAP调节γ-分泌酶加工APP和Notch 1的分子基础。我们将确定 HIF 1 α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： GSAP-和Hif 1 α-在AD小鼠模型中调节γ-分泌酶活性。本提案的长期目标目的是阐明γ-分泌酶调节的机制，并鉴定新的γ-分泌酶调节蛋白，并评估其与AD的相关性。我们的研究集中在γ-分泌酶调节的分子基础上，调节蛋白，并对理解疾病机制具有潜在的重大影响，开发治疗方法。