Targeting Multiple Diseases Through Gamma Secretase

通过伽玛分泌酶针对多种疾病

• 批准号: 7883268
• 负责人: BARBARA A OSBORNE
• 金额: $ 95.41万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883268
• 关键词: Targeting; Multiple; Diseases; Through; Gamma

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.

描述（由申请人提供）：本申请题为“通过γ-分泌酶靶向多种疾病”，将评估γ-分泌酶抑制剂针对中枢神经系统疾病、炎症反应和癌变的用途。构成本研究焦点的分子靶标γ-分泌酶因其在阿尔茨海默病（AD）发病机制中的重要性而成为学术界和工业界深入研究的主题。 γ-分泌酶有多个靶标，包括 Notch 蛋白家族。因此，γ-分泌酶的抑制可能对细胞生理学产生广泛的影响。已经开发了几类以不同效力和特异性抑制γ-分泌酶的药物。基于本申请中提供的初步数据，我们认为靶向γ-分泌酶可能对中枢神经系统、免疫系统以及正在发展的肿瘤产生广泛的影响，并进行实验来测试这些预测。在项目1中，我们将开发生物标志物来评估γ-分泌酶抑制对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γ-分泌酶抑制对多种体内免疫反应的影响，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γ-分泌酶抑制对维持肿瘤表型的影响。总体而言，该计划描述了一种跨学科方法，旨在确定多种疾病模型中针对酶活性、γ-分泌酶的功效。