NOVEL ANGIOGENESIS INHIBITOR FROM CARTILAGE

能够控制血管生成紊乱的药物的可用性对于那些以新生血管形成为主要作用的疾病具有广泛的适用性。抑制新生血管形成的疾病包括实体瘤的生长和转移、类风湿关节炎等。促进血管生成的病理事件包括心肌缺血和梗死，以及周围血管疾病。在后一种情况下，诱导新生血管，重建受损组织和发展侧支循环的能力是可取的。最近，我们的实验室发现了一种新的软骨来源的血管生成抑制剂，肌钙蛋白I （TnI）。我们已经证明，在两种独立的模型中，当局部和全身给药时，TnI是体内血管生成的有效抑制剂。此外，在不经动物预处理的情况下，全身给药时，TnI显著抑制了一种侵袭性最强的小鼠黑色素瘤细胞系B16BL6的转移。综上所述，这些研究表明，TnI可能在治疗以新血管化失调为特征的疾病方面具有宝贵的治疗潜力。TnI发挥其抗血管生成作用的机制尚不清楚。我们建议使用各种血管生成模型系统和一系列结构-功能分析来开始了解TnI在抑制新生血管方面的作用机制。我们还提出了一系列体内研究，通过评估其在体内抑制人类前列腺和乳腺肿瘤生长的能力，来验证TnI可能是一种治疗上有用的抗肿瘤药物的假设。此外，我们设计了实验来验证TnI可能是一种重要的内源性血管生长调节剂的假设，其作用是抑制受损肌肉组织（骨骼和/或心脏）损伤后自身血运重建的能力。这些假设将在以下特定目标的背景下进行测试：确定TnI抑制血管生成的生化和分子机制。目的：确定TnI的抗血管生成活性是否可以定位于一种特定的TnI。确定TnI作为抗肿瘤药物和血管生长生理调节剂的潜在治疗价值。

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.