Proteases Program

蛋白酶和癌症项目主要是一个基础科学项目，在过去的三年里，该项目成功地将转化和临床前研究整合到该项目中。该项目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/宿主相互作用，如何改变蛋白水解及其对抗蛋白酶治疗的影响;（2）有哪些机制（基因到蛋白质），调节蛋白酶的激活和抑制，以及如何使用这些来开发更有效的抑制剂或替代的抗蛋白酶策略用于体内;（3）蛋白酶及其内源性抑制剂如何在正常发育和非癌性病理过程中起作用，目的是鉴定新的治疗靶点;以及（4）什么是关键蛋白酶及其在细胞死亡和分化中的功能， 确定新目标的目标。五种内肽酶类的蛋白酶目前正在该计划中或通过癌症中心的跨计划合作进行研究。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进行结构-功能分析（例如，基质金属蛋白酶、纤溶酶原激活物抑制剂-1、maspin和半胱氨酸蛋白酶抑制剂的组织抑制剂），设计和测试已知的和新的基质金属蛋白酶、半胱氨酸（钙蛋白酶和组织蛋白酶）和天冬氨酸 蛋白酶和探索可调节蛋白酶相关功能的其它相互作用（例如，半乳糖凝集素-3，HB-EGF，膜联蛋白II异源四聚体，小窝）。转化研究工作的目标是：1）开发新型蛋白酶抑制剂作为潜在的治疗药物，2）确定可能调节蛋白酶相关功能的相互作用是否可以作为治疗干预的新靶点，以及3）开发用于蛋白酶活性体外和体内成像的新方法和探针。有四个合作子程序，以探索这些研究领域与相当大的交叉和合作之间的子程序和其他程序。

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.