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Selective modulation of Gamma-secretase processing through substrate binding

通过底物结合选择性调节伽马分泌酶加工

基本信息

批准号：
8414480
负责人：
THOMAS L KUKAR
金额：
$ 24.85万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8414480
关键词：
Abeta synthesis Adverse effects Affect Alzheimer&apos s Disease Amino Acids Amyloid beta-Protein Amyloid beta-Protein Precursor Anti-Inflammatory Agents Binding Biology Brain C-terminal Chemicals Chronic Cleaved cell Cognitive Complex Data Dementia Development Dimerization Drug Delivery Systems Elderly Enzymes Event Failure Future Goals Grant Human In Vitro Investigation Label Laboratories Lead Link Membrane Molecular Biology Mutation Patients Pattern Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase III Clinical Trials Placebos Positioning Attribute Process Production Property Protein Biochemistry Protein C Proteolysis Publishing Reporting Research Research Proposals Signal Pathway Signal Transduction Site Specificity Testing Therapeutic Work amyloid precursor protein processing base cognitive function crosslink design enzyme activity gamma secretase improved in vivo inhibitor/antagonist insight next generation notch protein novel presenilin prevent protective effect research study rho secretase small molecule

项目摘要

Numerous lines of evidence support the hypothesis that targeting A[342 is an ideal therapeutic strategy to prevent and/or treat Alzheimer's disease (AD), the major cause of dementia among the elderly. Chemicals called y-secretase modulators (GSMs), are being developed as AD therapeutics because they are able to selectively decrease Ap42. The first GSMs to be discovered were non-steroidal antiinflammatory drugs (NSAIDs), which lower Ap42 without inhibition of APP processing. As a whole GSMs minimally alter total Abeta production and instead shift where gamma-secretase cleaves Abeta. The mechanism of GSMs is still unknown although different explanations for their activity have been proposed including: 1) allosteric binding to y-secretase 2) inhibition of the Rho-ROCK signaling pathway 3) conformational changes in presenilin or 4) decreased dimerization of APP. We have recently discovered using novel GSM photoaffinity probes that these drugs do not label the y-secretase enzyme but instead modulate cleavage by binding to the substrate, APP. We hypothesize that binding of APP by GSMs shifts the position of APP-CTF in the membrane resulting in altered gamma-secretase cleavage. This hypothesis will be tested through the following specific aims: 1) investigate how substrate targeting by GSMs produces a shift in the cleavage pattern of Ap using a combination of molecular biology and protein biochemistry 2) determine the specificity of GSMs for affecting APP proteolysis by y-secretase in comparison to other substrates and 3) incorporate unnatural amino acids to study proteolysis of APPCTF by y-secretase. These studies will provide additional insight into how NSAIDs and other GSMs shift A(3 cleavage and how they exert their protective effects in vivo. This work will also guide future efforts to design more potent GSMs which will be useful as chemical probes for understanding the biology of ysecretase and as potential therapeutics for Alzheimer's disease.

许多证据支持这一假设，即靶向A[342]是一种理想的治疗策略