The objectives of this proposal are to elucidate the regulation of endogenous gamma-secretase and to understand the mechanism underlying Alzheimer's disease (AD) as well as to provide a molecular basis of drug development. gamma-Secretase as a drug target for Alzheimer's disease and cancer has been extensively investigated. Most of knowledge today on gamma-secretase mainly comes from studies that used an exogenous expression of one or more of the components of gamma-secretase in cellular models. Whether distinct gamma-secretase complexes and substrate specificity are associated with cell types, and possibly cell lineage and tissues is poorly understood. The proposed studies will investigate the regulation and function of the endogenous gamma-secretase complexes.
The first aim of this application is to elucidate the mechanism of gamma-secretase activity and specificity in epithelial, hematopoietic neuronal origins. The second specific aim is to examine the shape of the active site within the gamma-secretase complex and determine the stoichiometry of the gamma-secretase complexes isolated from epithelial, hematopoietic and neuronal cell lines. Lastly, the third aim is to determine the mechanism and specificity of gamma-secretase activity in the PS1 mutation knock-in and analyze active site structure and complex composition. The proposed studies will develop a comprehensive understanding of endogenous gamma-secretase and provide insights into the structure and function of gamma-secretase and may lead to a better understanding of gamma-secretase in AD and cancer as well as the development more effective treatment for AD, malignancies and other human disorders.

Public Health Relevance

gamma-Secretase has emerged as appealing drug target for Alzheimer disease and cancer. This proposal investigates the regulation and function endogenous gamma-secretase. The proposed studies will provide greater discernment of the function and specificity of gamma-secretase, and possibly lead to the development of more effective treatments for AD and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG026660-08
Application #
8531799
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Petanceska, Suzana
Project Start
2005-08-01
Project End
2016-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$354,323
Indirect Cost
$160,598
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Zhang, Xulun; Sullivan, Eric; Scimeca, Maggie et al. (2016) Evidence That the "Lid" Domain of Nicastrin Is Not Essential for Regulating γ-Secretase Activity. J Biol Chem 291:6748-53
Gilchrist, M Lane; Ahn, Kwangwook; Li, Yue-Ming (2016) Imaging and Functional Analysis of γ-Secretase and Substrate in a Proteolipobead System with an Activity-Based Probe. Anal Chem 88:1303-11
Paresi, Chelsea J; Liu, Qi; Li, Yue-Ming (2016) Benzimidazole covalent probes and the gastric H(+)/K(+)-ATPase as a model system for protein labeling in a copper-free setting. Mol Biosyst 12:1772-80
Gertsik, Natalya; Chau, De-Ming; Li, Yue-Ming (2015) γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase. ACS Chem Biol 10:1925-31
Dang, Shangyu; Wu, Shenjie; Wang, Jiawei et al. (2015) Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH. Proc Natl Acad Sci U S A 112:3344-9
Zhang, Xulun; Hoey, Robert; Koide, Akiko et al. (2014) A synthetic antibody fragment targeting nicastrin affects assembly and trafficking of γ-secretase. J Biol Chem 289:34851-61
Gertsik, Natalya; Chiu, Danica; Li, Yue-Ming (2014) Complex regulation of γ-secretase: from obligatory to modulatory subunits. Front Aging Neurosci 6:342
Villa, Jennifer C; Chiu, Danica; Brandes, Alissa H et al. (2014) Nontranscriptional role of Hif-1α in activation of γ-secretase and notch signaling in breast cancer. Cell Rep 8:1077-92
Gertsik, Natalya; Ballard, T Eric; Am Ende, Christopher W et al. (2014) Development of CBAP-BPyne, a probe for γ-secretase and presenilinase. Medchemcomm 5:338-341
Crump, Christina J; Johnson, Douglas S; Li, Yue-Ming (2013) Development and mechanism of γ-secretase modulators for Alzheimer's disease. Biochemistry 52:3197-216

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