The availability of agents which can control deregulated angiogenesis has broad applicability as a therapy for those diseases in which neovascularization plays a prominent role. Diseases in which it would be useful to inhibit neovascularization include solid tumor growth and metastasis, rheumatoid arthritis and others. Pathological events for which it would be useful to promote angiogenesis include myocardial ischemia and infarction, as well as peripheral vascular disease. In these latter cases, the ability to induce neovascularization, revascularize damaged tissue and develop the collateral circulation would be desirable. Recently, our laboratory has identified a novel cartilage-derived angiogenesis inhibitor, troponin I (TnI). We have shown that TnI is a potent inhibitor of angiogenesis in vivo, when delivered both locally and systemically in two independent models. Furthermore, when delivered systemically and without pre- treatment of the animals, TnI significantly inhibits the metastasis of one of the most highly invasive murine melanoma cell lines, B16BL6. Taken together, these studies suggest that TnI may have valuable therapeutic potential in the treatment of diseases characterized by deregulated neovascularization. The mechanism(s) by which TnI is exerting its anti-angiogenic effect is unknown. We are proposing to use a variety of angiogenesis models systems and a series of structure-function analyses to begin to understand TnI's mechanism of action with respect to its inhibition of neovascularization. We are also proposing a series of in vivo studies to test the hypothesis that TnI may be a therapeutically useful anti-tumor agent by evaluating its ability to inhibit human prostate and breast tumor growth in vivo. Further, we have designed experiments to test the hypothesis that TnI may be an important endogenous regulator of vascular growth by acting to suppress the ability of damaged muscle tissue (skeletal and/or cardiac) to revascularize itself post-injury. These hypotheses will be tested within the context of the following Specific Aims: To determine the biochemical and molecular mechanism(s) through which TnI inhibits angiogenesis. To determine whether the anti-angiogenic activity of TnI can be localized to a particular common of TnI. To determine the potential therapeutic value of TnI an anti-tumor agent and as a physiologic regulator of vascular growth.
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