Proteases Program

蛋白酶和癌症项目主要是一个基础科学项目，在过去三年中成功地将转化和临床前研究整合到该项目中。该项目的研究工作主要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，如何改变蛋白质水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（基因到蛋白质）是什么，以及如何利用这些机制开发更有效的抑制剂或在体内使用的替代抗蛋白酶策略；(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发挥作用，以确定新的治疗靶点；(4)在细胞死亡和分化过程中有哪些关键的蛋白酶及其功能

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.