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，即γ-分泌酶（一种具有几种生物学重要底物的多亚基膜内切割蛋白酶）的合理靶向可能被视为许多疾病的治疗靶点。该计划中的三个项目涉及γ-分泌酶抑制剂在乳腺癌（项目1）和移植物抗宿主病（项目2）中的应用，并提出生化策略，使我们能够更好地了解γ-分泌酶的作用机制（项目3）。这些项目的目标是更好地理解γ-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，该计划的主要研究者共同工作，共享数据并作为一个小组发表。该计划通过化学核心得到显着增强，该化学核心具有合成各种γ-分泌酶抑制剂的能力，允许该计划的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。这种方法将为与特定疾病相匹配的最佳GSI选择提供科学依据。

DESCRIPTION (provided by applicant): This Program proposes an overarching hypothesis that rational targeting of γ-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 γ-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 γ-secretase (Project 3). These projects are integrated with a goal of better understanding the mechanism of action of γ-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 γ-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.