REGULATION OF MACROPHAGE ANGIOGENIC ACTIVITY

巨噬细胞（Mphi）在诱导 在一些病理生理过程中， 调节这种特征表达的机制仍然很差， 明白 我们有证据表明，巨噬细胞（Mphi）激活导致 抑制基因的失活，其功能是：1）上调 新血管形成抑制剂的产生，所述新血管形成抑制剂是生物化学的， 免疫相关的，如果不相同的一部分， 多功能血小板反应蛋白（TSP）分子和2）下调 Mphi衍生的血管生成介质的表达。 定义了这些 控制表型，我们现在计划把注意力转向机制， 以及它们在体内的功能意义。 的 建议旨在： 1)评价TSP及其几种多肽的抗血管生成作用 碎片后，他们引入到实验伤口。 2)确定TSP的分布和特定细胞来源， 实验性创面与确定TSP水平的关系 以及使用原位血管生成的时间过程和幅度 杂交、免疫组织化学和氚标记胸苷 放射自显影 这种关系将在2中进一步评估。 血管生成依赖性人类疾病：类风湿性关节炎和慢性 牙周炎 3)确定TSP产生增加对血管生成的影响， 肿瘤细胞和活化的Mphi的活性， TSP cDNA，并评估连续内源性TSP产生的影响 在将这些转染的细胞引入 实验性伤口 4)确定控制表达的激活相关抑制因子 TSP和Mphi衍生的血管生成因子在以下水平起作用： 转录。 长期以来，抗血管生成一直被设想为治疗肿瘤的可能方法。 治疗血管生成依赖性疾病如实体瘤生长， 慢性炎症性疾病。 进一步的体内表征 这种抑制剂的意义及其抑制机制 Mphi血管生成活性的基因控制应该允许 治疗疾病过程的新策略， 去调节血管生成。

Macrophages (Mphi) play a central role in the induction of neovascularization in several pathophysiological processes yet the mechanisms which regulate expression of this trait are still poorly understood. We have evidence that macrophage (Mphi) activation results in the inactivation of a suppressor gene(s) that functions to: 1) up-regulate production of an inhibitor of neovascularization that is biochemically and immunologically related if not identical to a portion of the multifunctional thrombospondin (TSP) molecule and 2) down-regulate expression of Mphi-derived mediators of angiogenesis. Having defined these controls phenotypically we now plan to turn our attention to the mechanisms by which they operate and their functional significance in vivo. The proposal is designed to: 1) evaluate the anti-angiogenic effects of TSP and several of its peptide fragments following their introduction into experimental wounds. 2) identify the distribution and specific cellular sources of TSP in experimental wounds and determine the relationship between the level of TSP and the time course and magnitude of neovascularization using in situ hybridization, immunohistochemistry, and tritiated thymidine autoradiography. This relationship will be further evaluated in 2 angiogenesis-depended human diseases: rheumatoid arthritis and chronic periodontitis. 3) determine the effects of increased TSP production on the angiogenic activity of tumor cells and activated Mphi after transfection with a human TSP cDNA, and evaluate the effect of continuous endogenous TSP production on neovascularization after introducing these transfected cells into experimental wounds. 4) determine if the activation-linked suppressor that controls expression of TSP and Mphi-derived angiogenic factors functions at the level of transcription. Anti-angiogenesis has long been envisioned as a possible approach in the treatment of angiogenesis-depended disorders such as solid tumor growth and chronic inflammatory disease. Further characterization of the in vivo significance of this inhibitor and the mechanism underlying suppressor gene-control of Mphi angiogenic activity should permit the development of novel strategies for the treatment of disease processes characterized by deregulated angiogenesis.