Targeting Multiple Diseases Through Gamma Secretase

通过伽玛分泌酶针对多种疾病

• 批准号: 7258361
• 负责人: BARBARA A OSBORNE
• 金额: $ 96.39万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258361
• 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）：此申请名为“通过伽马 - 分泌酶靶向多种疾病”将评估使用γ-分泌酶抑制剂来靶向CNS疾病，炎症反应和致癌作用。构成这项研究重点的分子靶标，伽马分泌酶，一直是学术和工业社区对其在阿尔茨海默氏病（AD）发病机理中的重要性进行严格研究的主题。伽马分泌酶有几个靶标，包括蛋白质的凹陷家族。因此，抑制γ-分泌酶可能会对细胞生理产生广泛的影响。已经开发了几类药物，这些药物抑制具有可变效力和特异性的伽马分泌酶。基于本应用程序中介绍的初步数据，我们建议靶向γ-分泌酶可能在中枢神经系统，免疫系统以及开发肿瘤和姿势实验中具有面包范围的作用来测试这些预测。在项目1中，我们将开发生物标志物来评估伽马 - 分泌酶抑制对Notch的作用，并将这些数据与淀粉样蛋白蛋白的A -BetA片段相关联。还将研究Notch信号传导在脱髓鞘中的作用。在项目2中，将在各种体内免疫反应中研究γ-分泌酶抑制作用的作用，包括对两种病原体，抗体产生和自身免疫性的免疫反应。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，该方法旨在确定靶向多种疾病模型中的酶活性γ-分泌酶的功效。