Proteases Program

蛋白质和癌症计划主要是一个基础科学计划，在过去三年中成功地将翻译和临床前研究整合到该计划中。该计划的研究工作集中在四个主要问题上：(1)肿瘤微环境，包括肿瘤/宿主的相互作用，如何改变蛋白分解及其对抗蛋白酶治疗的影响；(2)调节蛋白酶激活和抑制的机制(基因与蛋白)是什么，以及如何利用这些机制来开发更有效的抑制剂或替代体内使用的抗蛋白酶策略；(3)为了寻找新的治疗靶点，蛋白酶及其内源性抑制物如何在正常发育和非癌症的病理过程中发挥作用；以及(4)在细胞死亡和分化中，关键的蛋白酶及其功能是什么？ 确定新目标的目标。五种内肽酶类别的蛋白水解酶目前正在该计划中或通过癌症中心的项目间合作进行研究。在蛋白酶抑制剂方面，项目成员正在对内源性蛋白酶抑制剂(例如，基质金属蛋白酶的组织抑制剂、纤溶酶原激活物抑制物-1、Maspin和半胱氨酸酶)进行结构-功能分析，设计和测试已知的和新型的基质金属蛋白酶、半胱氨酸(钙蛋白酶和组织蛋白酶)和天冬氨酸氨基转移酶的合成抑制剂 并探索其他可能调节蛋白水解酶相关功能的相互作用(例如，Galectin-3、HB-EGF、Annexin II异四聚体、小窝)。翻译研究的努力主要集中在：1)开发新的蛋白水解酶抑制剂作为潜在的治疗药物；2)确定可能调节蛋白水解酶相关功能的相互作用是否可以作为治疗干预的新靶点；3)开发新的方法和探针，用于体外和体内的蛋白水解酶活性成像。有四个协作子计划来探索这些研究领域，子计划和其他计划之间有相当大的交叉和协作。

The Proteases and Cancer Program has primarily been a basic science program that has successfully worked to integrate translational and preclinical research into the program during the past three years. The research efforts of this program have concentrated on four major questions: (1) how the tumor microenvironment, including tumor/host interactions, alters proteolysis and the impact of this on anti-protease therapies; (2) what are the mechanisms (gene to protein) that regulate activation and inhibition of proteases and how can these be used to develop more efficacious inhibitors or alternative anti-protease strategies for use in vivo; (3) how proteases and their endogenous inhibitors function in normal developmental and non-cancerous pathological processes with the goal of identifying new therapeutic targets; and (4) what are the critical proteases and their functions in cell death and differentiation, also with the goal of identifying new targets. Proteases of the five endopeptidase classes are currently under study in the Program or through inter-programmatic collaborations in the Cancer Center. In terms of protease inhibitors, program members are performing structure-function analyses on endogenous protease inhibitors (e.g., tissue inhibitors of matrix metalloproteinases, plasminogen activator inhibitor-1, maspin, and cystatins), designing and testing known and novel synthetic inhibitors for matrix metalloproteinases, cysteine (calpain and cathepsin) and aspartic proteases and exploring other interactions that may modulate protease-associated functions (e.g., galectin-3, HB-EGF, annexin II heterotetramer, caveolae). Translational research efforts are directed toward: 1) development of novel protease inhibitors as potential therapeutic agents, 2) determining whether interactions that may modulate protease-associated functions might serve as novel targets for therapeutic intervention, and 3) developing novel methods and probes for in vitro and in vivo imaging of protease activity. There are four collaborative subprograms to explore these research areas with considerable crossover and collaboration among the subprograms and other Programs.