Macrophage Pericellular Proteinase Cascade

巨噬细胞胞周蛋白酶级联

• 批准号: 7160572
• 负责人: DOMENICK J FALCONE
• 金额: $ 39.82万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-08 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7160572
• 关键词: ANXA2 gene; Address; Affect; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Binding; Binding Sites; CCL2 gene; Cell Line; Cell surface; Cells; Chemotaxis; Chronic; Collagen; Complex; Development; Disease; Endopeptidases; Extracellular Matrix; Extracellular Matrix Degradation; Family; Family member; Fibrin; Foreign Bodies; Gelatinase B; Generations; Granuloma; Granuloma, Foreign-Body; Immigration; Immunoglobulin G; In Vitro; Inflammation; Inflammatory; Kinetics; Knockout Mice; Kringles; Liquid substance; Macrophage Activation; Matrix Metalloproteinases; Membrane; Membrane Biology; Modeling; Mus; Mutant Strains Mice; Peptide Hydrolases; Peritonitis; Pharmacia brand of estropipate; Phase; Plasmin; Plasminogen; Play; Proteolysis; Purpose; Regulation; Research Design; Role; Site; Surface; System; Testing; Thioglycolates; Tissues; Urokinase; base; in vivo; inhibitor/antagonist; macrophage; member; migration; monocyte; novel therapeutics; research study; therapeutic effectiveness; therapeutic target

DESCRIPTION (provided by applicant): The synthesis and/or activation of matrix degrading proteinases play an essential role in the migration of monocytes and macrophages through tissue. Foremost among these proteinases is the urokinase type plasminogen activator (uPA)-plasminogen system. Plasmin binds to and degrades fibrin and several components of the extracellular matrix (ECM). In addition, plasmin activates several members of the family of matrix metalloproteinases (MMP), which are responsible for the degradation of collagen and other components of the ECM. Despite earlier observations that binding to the cell surface imparts a kinetic advantage to plasminogen activation and protection of plasmin from inhibition, the biology of membrane-bound plasmin remains largely unexplored, and its role as a therapeutic target in chronic inflammatory diseases remains untested. The overall purpose of experiments described in this proposal is to test the hypothesis that plasmin binding sites on the surface of macrophages are the primary regulator of their pericellular proteinase cascade, and blocking plasmin(ogen) binding to their surface is an effective strategy to reduce macrophage accumulation, and its sequelae in chronic inflammatory diseases. Two complimentary strategies are proposed: (1) Utilizing mice deficient in a defined plasminogen binding site (annexin II), we will directly determine the role of plasmin binding sites in macrophage activation of MMP-9, degradation of ECM and MCP-l-dependent migration through ECM in vitro (Specific Aim 1). Also, we will determine the effect of annexin II deficiency on macrophage recruitment in vivo utilizing thioglycollate-induced peritonitis and foreign body-induced granuloma models and recruitment to atherosclerotic lesions in Apo E-/- IAnx II-/- mice (Specific Aim 2). (2) We will determine the therapeutic effectiveness of an inactive cell-binding fragment of plasminogen to block macrophage activation of MMP-9, ECM degradation and MCP-1- dependent migration through ECM in vitro, as well as macrophage recruitment in vivo in the thioglycollate-induced peritonitis and foreign body-induced granuloma models (Specific Aim 3). We believe that the results of proposed in vitro and in vivo experiments will provide a basis for novel therapeutic strategies targeting plasmin-binding sites to modulate chronic inflammation, tissue remodeling and atherosclerosis.

描述（由申请方提供）：基质降解蛋白酶的合成和/或活化在单核细胞和巨噬细胞通过组织的迁移中发挥重要作用。这些蛋白酶中最重要的是尿激酶型纤溶酶原激活物（uPA）-纤溶酶原系统。纤溶酶结合并降解纤维蛋白和细胞外基质（ECM）的几种组分。此外，纤溶酶激活基质金属蛋白酶（MMP）家族的几个成员，其负责胶原蛋白和ECM的其他组分的降解。尽管早期观察到与细胞表面的结合赋予纤溶酶原活化动力学优势并保护纤溶酶免受抑制，但膜结合纤溶酶的生物学仍然在很大程度上未被探索，并且其作为慢性炎性疾病中的治疗靶点的作用仍然未被测试。本提案中描述的实验的总体目的是检验以下假设：巨噬细胞表面上的纤溶酶结合位点是其细胞周蛋白酶级联的主要调节剂，阻断纤溶酶（原）与其表面结合是减少巨噬细胞蓄积及其在慢性炎症性疾病中的后遗症的有效策略。提出了两种互补策略：（1）利用限定的纤溶酶原结合位点（膜联蛋白II）缺陷的小鼠，我们将直接确定纤溶酶结合位点在MMP-9的巨噬细胞活化、ECM的降解和MCP-1依赖性通过ECM的体外迁移中的作用（具体目标1）。此外，我们还将利用巯基乙酸盐诱导的腹膜炎和异物诱导的肉芽肿模型以及Apo E-/- IAnx II-/-小鼠动脉粥样硬化病变的募集，确定膜联蛋白II缺乏对体内巨噬细胞募集的影响（具体目标2）。(2)我们将确定纤溶酶原的无活性细胞结合片段在体外阻断MMP-9的巨噬细胞活化、ECM降解和MCP-1依赖性通过ECM的迁移以及在巯基乙酸盐诱导的腹膜炎和异物诱导的肉芽肿模型中体内巨噬细胞募集的治疗有效性（具体目标3）。 我们相信，在体外和体内实验的结果将提供一个新的治疗策略靶向纤溶酶结合位点调节慢性炎症，组织重塑和动脉粥样硬化的基础。

项目成果

The annexin A2/S100A10 system in health and disease: emerging paradigms.

• DOI: 10.1155/2012/406273
• 发表时间: 2012
• 期刊: Journal of biomedicine & biotechnology
• 作者: Hedhli N;Falcone DJ;Huang B;Cesarman-Maus G;Kraemer R;Zhai H;Tsirka SE;Santambrogio L;Hajjar KA
• 通讯作者: Hajjar KA

Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: evidence for the role of TNF-alpha and cyclooxygenase-2.

• DOI: 10.4049/jimmunol.0901925
• 发表时间: 2009-12-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Steenport M;Khan KM;Du B;Barnhard SE;Dannenberg AJ;Falcone DJ
• 通讯作者: Falcone DJ