NOVEL ANGIOGENESIS INHIBITOR FROM CARTILAGE

可以控制去调节的血管生成的试剂的可用性具有广泛的适用性，作为新血管形成在其中起重要作用的那些疾病的治疗。抑制新血管形成将是有用的疾病包括实体瘤生长和转移、类风湿性关节炎等。 促进血管生成有用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，需要诱导新血管形成、使受损组织再血管化并形成侧支循环的能力。最近，我们的实验室已经确定了一种新的软骨源性血管生成抑制剂，肌钙蛋白I（TnI）。 我们已经表明，TnI是一种有效的抑制血管生成在体内，在两个独立的模型中，在本地和系统交付时。此外，当全身递送并且不对动物进行预处理时，TnI显著抑制最高度侵袭性的鼠黑素瘤细胞系之一B16 BL 6的转移。 总之，这些研究表明，肌钙蛋白I可能具有宝贵的治疗潜力，在治疗疾病的特点是失调的新血管形成。TnI发挥其抗血管生成作用的机制尚不清楚。 我们建议使用多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抑制新生血管形成的作用机制。 我们还提出了一系列的体内研究，以测试的假设，TnI可能是一种治疗上有用的抗肿瘤药物，通过评估其抑制人体前列腺和乳腺肿瘤生长的能力在体内。 此外，我们已经设计了实验来测试这一假设，即TnI可能是血管生长的重要内源性调节剂，其作用是抑制受损肌肉组织（骨骼肌和/或心脏）在损伤后自身再血管化的能力。 这些假设将在以下特定目的的背景下进行检验：确定TnI抑制血管生成的生化和分子机制。确定TnI的抗血管生成活性是否可以定位于TnI的特定共同点。 确定TnI作为一种抗肿瘤药物和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.