Regulation and Function of Gamma-Secretase

描述(申请人提供)：这项建议的目的是阐明内源性伽马分泌酶的调节，了解阿尔茨海默病(AD)的发病机制，并为药物开发提供分子基础。伽马分泌酶作为治疗阿尔茨海默病和癌症的药物靶点已经得到了广泛的研究。今天关于伽马分泌酶的大部分知识主要来自于在细胞模型中使用外源表达伽马分泌酶的一个或多个成分的研究。不同的伽马-分泌酶复合体和底物特异性是否与细胞类型、可能的细胞谱系和组织相关还知之甚少。拟议的研究将探讨内源性伽玛-分泌酶复合体的调节和功能。这项应用的第一个目的是阐明在上皮性和造血性神经元起源中伽马分泌酶的活性和特异性的机制。第二个具体目的是检查伽马分泌酶复合体内活性部位的形状，并确定从上皮细胞、造血细胞和神经细胞系分离出来的伽马分泌酶复合体的化学计量比。最后，第三个目的是确定PS1突变敲入中伽玛分泌酶活性的机制和特异性，并分析活性部位结构和络合物组成。这些研究将对内源性伽玛分泌酶有一个全面的了解，并提供对伽马分泌酶的结构和功能的洞察，并可能有助于更好地理解AD和癌症中的伽马分泌酶，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.