There has been an intense effort to develop clinically useful pharmacologic inhibitors of matrix proteases in order to reduce aberrant enzyme activity in many diseases. Although these efforts have resulted in a multitude of promising compounds, the vast majority of the drugs block proteases critical for the physiologic function of non-targeted cells/tissues. In this COBRE Core, the investigators will use in vitro models and a variety of cell types and protease stimuli to study the effects of existing and new synthetic protease inhibitors to be designed and synthesized by Drs. Sibi, Rodgers, Cook and Mallik and Balaz (Projects 1-3). These inhibitors will target two types of matrix enzymes: matrix metalloproteinases and serine proteases. The core's specific aims are to establish cell culture assays to measure the cytotoxicity and efficacy of proteinase antagonists. Efficacy will be assessed through in vitro invasion assays. Eight cell types will be used in these in vitro assays in order to potentially identify inhibitors which are effective at reducing cell invasion in one cell environment vs others. The Core will communicate the results of testing back to the investigators in projects 1-3 in order to allow them refine the design of promising preliminary compounds. During the later portion of the grant, the Core will progress to animal studies (Years 4 and 5) in order to assess efficacy of selected protease antagonists developed during the course of the grant which show promise in the in vitro assays. In addition to these specific aims, the investigators anticipate that the Core will develop, refine and expand its spectrum of assays to encompass related enzyme systems such as disintegrins and angiotensin converting enzymes. This core facility will provide the PI, Dr. Seligal, with an excellent array of established in vitro techniques, well-trained personnel and an experienced collaborator in the field of animal studies. Thus, this core will be of tremendous benefit to Dr. Seligal's research on the regulation of matrix metalloproteinases in prostate cancer and will fulfill a goal of the COBRE RFA to raise the research capability of junior investigators so that they can successfully compete for funding.
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