Targeting Multiple Diseases Through Gamma Secretase

描述（由申请人提供）：本项目提出了一个总体假设，合理的目标是？-secretase是一种多亚基膜内切割蛋白酶，具有几种重要的生物学底物，可被认为是许多疾病的治疗靶点。本计划的三个项目涉及使用？-分泌酶抑制剂在乳腺癌（项目1）和移植物抗宿主病（项目2）中的作用，并提出生化策略，使我们能够更好地了解？-分泌酶（项目3）。这些项目的目标是更好地理解？-分泌酶抑制在正常，以及，疾病设置。在过去的六年里，这个项目的主要研究人员一起工作，共享数据并作为一个团队发表。该计划是由一个化学核心，已被证明有能力合成各种各样的？-分泌酶抑制剂，允许计划成员在不受商业限制的环境中探索这些抑制剂的生物学特性。这种方法将为选择与特定疾病相匹配的最佳GSI提供科学依据。

DESCRIPTION (provided by applicant): This Program proposes an overarching hypothesis that rational targeting of ?-secretase, a multi-subunit intramembrane cleaving protease that has several biologically important substrates, may be considered as a therapeutic target for a number of diseases. The three projects in this Program address the use of ?-secretase inhibitors in breast cancer (Project 1), and graft-versus-host disease (Project 2), and propose biochemical strategies to enable us to better understand the mechanism of action of ?-secretase (Project 3). These projects are integrated with a goal of better understanding the mechanism of action of ?-secretase inhibition in normal, as well as, disease settings. The Principal Investigators of this Program have worked together, shared data and published as a group for the past six years. The Program is significantly enhanced by a Chemistry Core that has the proven ability to synthesize a wide variety of ?-secretase inhibitors that allow members of the Program to explore the biological properties of these inhibitors in an environment free from commercial restriction. Such an approach will provide a scientific basis for optimal GSI selection matched to a particular disease.