Targeting Multiple Diseases Through Gamma Secretase

描述(由申请人提供)：本计划提出了一个重要的假设，即合理靶向β-分泌酶，一种具有多个生物重要底物的多亚单位膜内裂解酶，可被认为是许多疾病的治疗靶点。本计划中的三个项目涉及β-分泌酶抑制剂在乳腺癌(项目1)和移植物抗宿主病(项目2)中的使用，并提出生化策略使我们能够更好地了解β-分泌酶的作用机制(项目3)。这些项目的目的是为了更好地了解β-分泌酶抑制在正常和疾病环境中的作用机制。在过去的六年里，该项目的主要研究人员一直在一起工作，共享数据，并作为一个小组发表文章。该计划得到了一个化学核心的显著增强，该核心具有合成多种分泌酶抑制剂的能力，使该计划的成员能够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.