REGULATION OF MACROPHAGE ANGIOGENIC ACTIVITY

巨噬细胞(Mphi)在诱导骨髓瘤的发生中起着核心作用。 几种病理生理过程中的新生血管 调节这一特性表达的机制仍然很差。 明白了。我们有证据表明巨噬细胞(Mphi)激活会导致 一种抑制基因(S)的失活，其作用是：1)上调 生产一种新的血管生成抑制物，其生化和 在免疫上相关，如果不完全相同的话 多功能血栓反应蛋白(TSP)分子与2)下调 Mphi来源的血管生成介质的表达。我已经定义了这些 控制表型我们现在计划将注意力转向机制 它们的运作方式以及它们在体内的功能意义。这个 建议书旨在： 1)评价TSP及其几种多肽的抗血管生成作用 在进入实验伤口后的碎片。 2)确定TSP的分布和特定的细胞来源 实验性创伤与测定TSP水平的关系 原位观察新生血管形成的时程和大小 杂交、免疫组织化学和氚胸苷 放射自显影。这一关系将在2年中进一步评估 依赖血管生成的人类疾病：类风湿性关节炎和慢性 牙周炎。 3)确定TSP产量增加对血管生成的影响 转染人后肿瘤细胞的活性及活化的Mphi TSP基因，并评价持续内源性TSP产生的效果 转基因细胞导入后新生血管形成的研究 实验性伤口。 4)确定控制表达的激活连锁抑制子 TSP和Mphi衍生的血管生成因子在血管生成水平上的作用 抄写。 长期以来，抗血管生成一直被认为是一种可能的治疗方法 治疗血管生成依赖型疾病，如实体瘤生长和 慢性炎症性疾病体内实验的进一步表征 该抑制物的意义及其作用机制 Mphi血管生成活性的基因控制应允许 治疗疾病过程的新战略，其特点是 不受管制的血管生成。

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.