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.
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.
|Villa, Jennifer C; Chiu, Danica; Brandes, Alissa H et al. (2014) Nontranscriptional role of Hif-1? in activation of ?-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 ?-secretase and presenilinase. Medchemcomm 5:338-341|
|Crump, Christina J; Johnson, Douglas S; Li, Yue-Ming (2013) Development and mechanism of ýý-secretase modulators for Alzheimer's disease. Biochemistry 52:3197-216|
|Chau, De-Ming; Crump, Christina J; Villa, Jennifer C et al. (2012) Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of ?-secretase. J Biol Chem 287:17288-96|
|Crump, Christina J; am Ende, Christopher W; Ballard, T Eric et al. (2012) Development of clickable active site-directed photoaffinity probes for ?-secretase. Bioorg Med Chem Lett 22:2997-3000|
|Renzi, Fabiana; Zhang, Xulun; Rice, William J et al. (2011) Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy. J Biol Chem 286:21440-9|
|Tian, Yuan; Crump, Christina J; Li, Yue-Ming (2010) Dual role of alpha-secretase cleavage in the regulation of gamma-secretase activity for amyloid production. J Biol Chem 285:32549-56|
|Yang, Ting; Arslanova, Dilyara; Xu, Xiaoyin et al. (2010) In vivo manifestation of Notch related phenotypes in zebrafish treated with Alzheimer's amyloid reducing gamma-secretase inhibitors. J Neurochem 113:1200-9|
|Tian, Yuan; Bassit, Bhramdeo; Chau, Deming et al. (2010) An APP inhibitory domain containing the Flemish mutation residue modulates gamma-secretase activity for Abeta production. Nat Struct Mol Biol 17:151-8|
|Kounnas, Maria Z; Danks, Anne M; Cheng, Soan et al. (2010) Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron 67:769-80|
Showing the most recent 10 out of 21 publications