Regulation and Function of Gamma-Secretase

描述（由申请人提供）：本申请的目的是阐明内源性γ -分泌酶的调控，了解阿尔茨海默病（AD）的机制，并为药物开发提供分子基础。γ -分泌酶作为治疗阿尔茨海默病和癌症的药物靶点已被广泛研究。目前关于γ -分泌酶的大部分知识主要来自于在细胞模型中使用一种或多种γ -分泌酶成分的外源性表达的研究。不同的γ -分泌酶复合物和底物特异性是否与细胞类型，以及可能的细胞谱系和组织相关尚不清楚。本研究将探讨内源性γ -分泌酶复合物的调控和功能。本应用程序的第一个目的是阐明γ -分泌酶活性和特异性在上皮，造血神经元起源的机制。第二个特定目的是检查γ -分泌酶复合物内活性位点的形状，并确定从上皮、造血和神经细胞系中分离的γ -分泌酶复合物的化学计量学。最后，第三个目标是确定PS1突变敲入中γ -分泌酶活性的机制和特异性，并分析活性位点结构和复合物组成。本研究将全面了解内源性γ -分泌酶，深入了解γ -分泌酶的结构和功能，并有助于更好地了解γ -分泌酶在AD和癌症中的作用，以及开发更有效的治疗AD、恶性肿瘤和其他人类疾病的方法。

DESCRIPTION (provided by applicant): 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.