Profiling y-secretase activity and inhibition

γ-分泌酶是一种迷人的多亚单位膜内裂解酶，目前正被认为是许多疾病的治疗靶点。主要是因为伽玛分泌酶是阿尔茨海默病(AD)的治疗靶点，已经开发了许多GSI，有效地抑制人类伽玛分泌酶的切割。在患有AD的人类中，目前GSI的长期治疗似乎具有基于机制的副作用，将最大耐受剂量限制在长期AB降低的程度可能不足以对有症状的患者产生临床影响的程度。然而，正如项目1和2所阐述的，由于它在调节来自其他蛋白质的信号事件中的作用，主要集中在Notch信号；伽马分泌酶是癌症和免疫性疾病的治疗靶点，并且很可能成为其他疾病的靶标，只要治疗窗口是急性、亚急性或间歇性的。鉴于本提案项目1和2中的初步和已公布的数据，以及其他支持将地理信息系统重新用于多种疾病适应症的数据，有必要对这一正在进行的重新调整用途的努力进行进一步的探索。当考虑改变GSI的用途时，一个主要的挑战是，对GSI的研究主要集中在APP和Notch 1上。在AD中，GSIs被认为是AB抑制剂，在癌症中被认为是Notch 1抑制剂，但到目前为止，GSI对另外近100种底物的作用如何？这些卵裂与正在研究的系统的生物学相关还是无关？事实上，该项目的主要工作假设是，为了了解伽马分泌酶的生物学作用并适当地重新使用针对给定疾病适应症的GSI，需要更全面地了解伽马分泌酶的活性和GSI的底物抑制谱。建议的研究将使我们能够方便地评估更广泛的伽马分泌酶底物的裂解；指导GSI作为癌症、GVHD和其他新兴适应症的治疗药物的再利用努力，并使我们能够确定伽马分泌酶裂解是否在衰老或AD中发生改变。

Gamma-secretase is a fascinating multi-subunit intramembrane cleaving protease that is now being considered as a therapeutic target for a number of diseases. Primarily because gamma-secretase was a therapeutic target in Alzheimer's disease (AD), a number of GSIs have been developed that effectively inhibit gamma-secretase cleavage in humans. In humans with AD, long-term treatment with current GSIs appears to have mechanism based side-effects that limit the maximum tolerable dose to the point where the extent of long-term AB lowering is likely to be insufficient to have clinical impact in symptomatic patients. However, as elaborated on in Projects 1 and 2, because of its role in mediating signaling events from other proteins, with a primary focus on Notch signaling; gamma-secretase is a therapeutic target in cancer and immunologic disease and may very well be a target in other diseases, as long as the treatment window is acute, subacute or intermittent. Given the preliminary and published data in Projects 1 and 2 of this proposal as well as data from others supporting the repurposing of GSIs for multiple disease indications, further exploration of this ongoing repurposing effort is warranted. A major challenge when considering repurposing of GSIs is that the study of gamma-secretase cleavage has been dominated by its focus on APP and Notch 1. GSIs in AD are thought of as AB inhibitors and in cancer as Notch 1 inhibitors, but what about the GSI action on the nearly 100 additional substrates identified to date? Are these cleavages relevant or irrelevant to the biology of the system being investigated? Indeed, the major working hypothesis of this project is that in order to understand the biological role of gamma-secretase and appropriately repurpose GSIs for a given disease indication a fuller appreciation of gamma-secretase activity and the substrate inhibitory profiles of GSIs are needed. The studies proposed will enable facile assessment of cleavage of a broader repertoire of gamma-secretase substrates; guide the repurposing efforts for GSIs as therapeutics in cancer, GVHD and other emerging indications, and enable us to determine whether gamma-secretase cleavage is altered in aging or AD.