MACROPHAGE PROTEASE CASCADE AND VASCULAR REMODELING

描述(改编自调查人员摘要)：表达 巨噬细胞基质降解酶可能影响动脉粥样硬化病变 通过释放基质结合的生长因子和斑块来发育 不稳定。在这方面，巨噬细胞表达的尿激酶型 纤溶酶原激活物(UPA)及随后的纤溶酶原激活作用 在基质降解中起核心作用。纤溶酶降解基质成分和 使基质降解金属蛋白酶(MMPs)失活。对此进行监管 Protease Casade是这项持续拨款申请的主题。这个 本提案的目的是：1)确定合作伙伴的作用 巨噬细胞uPA和基质金属蛋白酶在组织重塑和释放中的表达 与矩阵有关的增长因素。2)确定细胞外基质的作用 调节巨噬细胞uPA和基质金属蛋白酶的表达。矩阵组件， 细胞受体和信号转导通路 UPA和基质金属蛋白酶的基质诱导作用将被确认。这一机制通过它 基质金属蛋白酶调节巨噬细胞uPA的表达 下定决心。3)确定转化生长因子-β在巨噬细胞介导的组织中的作用 改建。依赖单核细胞分化的转化生长因子-β受体的表达 将表征并与转化生长因子-β诱导的血管内皮细胞的改变相关 UPA和基质金属蛋白酶的表达。差异性转化生长因子-β受体的作用 巨噬细胞uPA和基质金属蛋白酶的表达将通过 野生型和突变型I、II受体转染细胞。4) 确定膜联蛋白II在细胞周纤溶酶调节中的作用 活动。细胞表面膜联蛋白II在纤溶酶调节中的作用 自身蛋白分解和含有kringle片段的形成将是 利用野生型和突变型膜联蛋白II转基因细胞进行鉴定。 自身蛋白分解在巨噬细胞迁移调节中的作用 基质降解和释放的基质结合生长因子将 下定决心。这些研究的结果将有助于阐明这些机制，通过 哪些巨噬细胞协调基质降解并为我们提供新的 动脉粥样硬化及其他疾病的介入治疗策略 慢性炎症性疾病。

DESCRIPTION (Adapted from Investigator's Abstract): Expression of matrix-degrading proteases by macrophages may effect atherosclerotic lesion development through the release of matrix-bound growth factors and plaque destabilization. In this regard, macrophage expression of urokinase-type plasminogen activator (uPA) and subsequent plasminogen activation plays a central role in matrix degradation. Plasmin degrades matrix components and deactivates matrix-degrading metalloproteinases (MMP). Regulation of this protease cascade is the subject of this continuing grant application. The aims of this proposal are to: 1) Determine the cooperative role of macrophage uPA and MMP expression in tissue remodeling and release of matrix-bound growth factors. 2) Determine the role of extracellular matrix in the regulation of macrophage uPA and MMP expression. Matrix components, cellular receptors and signal transduction pathways that mediate matrix-induction of uPA and MMP will be identified. The mechanism by which MMP regulate matrix-induction of macrophage uPA expression will be determined. 3) Determine the role of TGF-beta in macrophage mediated tissue remodeling. Monocyte differentiation-dependent TGF-beta receptor expression will be characterized and correlated with TGF-beta induced alterations in uPA and MMP expression. The role of differential TFG-beta receptor expression in macrophage uPA and MMP expression will be determined utilizing cells transfected with wild type and mutant type I and II receptors. 4) Determine the role of annexin II in the regulation of pericellular plasmin activity. The role of cell surface annexin II in the regulation of plasmin autoproteolysis and formation of kringle containing fragments will be determined utilizing cells transfected with wild type and mutant annexin II. The role of autoproteolysis in the regulation of macrophage transmigration, matrix degradation and release of matrix-bound growth factors will be determined. Results of these studies will help elucidate the mechanisms by which macrophages orchestrate matrix degradation and provide us with novel interventional strategies for the treatment of atherosclerosis and other chronic inflammatory diseases.