Targeting Multiple Diseases Through Gamma Secretase

描述(由申请人提供)：这项题为“通过伽马分泌酶靶向多种疾病”的申请将评估伽玛分泌酶抑制剂用于靶向中枢神经系统疾病、炎症反应和致癌的使用。形成本研究重点的分子靶点--γ-分泌酶，因其在阿尔茨海默病(AD)发病机制中的重要作用而受到学术界和工业界的广泛研究。伽马分泌酶有几个靶点，包括Notch蛋白家族。因此，抑制γ-分泌酶可能会对细胞生理学产生广泛的影响。已经开发出几类抑制伽玛分泌酶的药物，其效力和特异性各不相同。根据本申请中提供的初步数据，我们认为靶向伽马分泌酶可能在中枢神经系统、免疫系统以及肿瘤的发生中具有广泛的影响，并提出实验来验证这些预测。在项目1中，我们将开发生物标记物来评估抑制伽马分泌酶对Notch的影响，并将这些数据与淀粉样前体蛋白A-β片段的减少相关联。Notch信号在脱髓鞘中的作用也将被研究。在项目2中，将研究伽马分泌酶抑制在体内各种免疫反应中的作用，包括对两种病原体的免疫反应，抗体产生和自身免疫。在项目3中，我们将确定伽玛分泌酶抑制在维持肿瘤表型方面的作用。总体而言，该计划描述了一种跨学科的方法，旨在确定在多种疾病模型中靶向一种酶活性，即伽马分泌酶的有效性。

DESCRIPTION (provided by applicant): This application entitled "Targeting multiple diseases through gamma -secretase" will evaluate the use of gamma -secretase inhibitors to target CNS disease, inflammatory responses and carcinogenesis. The molecular target that forms the focus of this study, gamma -secretase, has been the subject of intense investigation by the academic and industrial communities for its importance in the pathogenesis of Alzheimer's disease (AD). Gamma-secretase has several targets including the Notch family of proteins. Therefore inhibition of gamma -secretase is likely to have broad effects on cellular physiology. Several classes of drugs have been developed which inhibit gamma -secretase with variable potency and specificity. Based on preliminary data presented in this application, we suggest that targeting gamma -secretase is likely to have bread ranging effects in the CNS, immune system as well as in developing tumors and pose experiments to test these predictions. In Project 1, we will develop biomarkers to evaluate the effect of gamma -secretase inhibition on Notch and correlate these data with reduction in the A-beta fragment of amyloid precursor protein. The role of Notch signaling in demyelination also will be studied. In Project 2, the effects of gamma -secretase inhibition will be studied in a variety of in vivo immune responses including immune response to two pathogens, antibody production and autoimmunity. In Project 3, we will determine the effect of gamma -secretase inhibition on the maintenance of the neoplastic phenotype. Overall this Program describes an interdisciplinary approach directed at establishing the efficacy of targeting an enzymatic activity, gamma -secretase in multiple disease models.