NOVEL ANGIOGENESIS INHIBITOR FROM CARTILAGE

目前已有的抑制血管生成的药物在治疗以新生血管为主的疾病方面具有广泛的应用前景。对抑制新生血管有用的疾病包括实体瘤生长和转移、类风湿性关节炎等。有助于促进血管生成的病理事件包括心肌缺血和梗塞，以及外周血管疾病。在后一种情况下，有能力诱导新生血管、重建受损组织和发展侧支循环将是可取的。最近，我们实验室发现了一种新的软骨源性血管生成抑制剂--肌钙蛋白I(TnI)。我们已经证明，当在两个独立的模型中局部和系统地给药时，TnI是一种有效的体内血管生成抑制因子。此外，当系统地给药并且没有对动物进行预处理时，TnI显著地抑制了最高侵袭性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可能在治疗以去调节新生血管为特征的疾病方面具有有价值的治疗潜力。TnI发挥抗血管生成作用的机制(S)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抑制新生血管的作用机制。我们还提出了一系列体内研究，通过评估TnI在体内抑制人类前列腺和乳腺肿瘤生长的能力，来验证TnI可能是一种治疗有用的抗肿瘤药物的假设。此外，我们设计了实验来验证这一假设，即TnI可能是血管生长的重要内源性调节因子，通过抑制受损肌肉组织(骨骼和/或心脏)在损伤后重新血管化的能力来发挥作用。这些假说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(S)。目的：确定TnI的抗血管生成活性是否可定位于TnI的特定共同点。目的：确定抗肿瘤药物TnI作为血管生长的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.