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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：
10538600
负责人：
YUEMING LI
金额：
$ 84.9万
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538600
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.

γ-分泌酶的催化亚基-早老素-1 （PS1）或早老素-2 （PS-2）的突变可导致早期的-