Arthritic Disease and the Hemostatic System

关节炎疾病和止血系统

• 批准号: 6997796
• 负责人: JAY L DEGEN
• 金额: $ 33.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6997796
• 关键词: arthritis; blood coagulation; blood proteins; disease /disorder model; fibrin; fibrinogen; fibrinogen receptors; gene mutation; genetically modified animals; hemostasis; hirudins; inflammation; integrins; laboratory mouse; pathologic process; plasmin; plasminogen; plasminogen activator; proteolysis; rheumatoid arthritis; thrombin

DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the role of key hemostatic factors in inflammatory joint disease. The widespread deposition of fibrin (ogen) and fibrin degradation products within joints is one of the most conspicuous features of rheumatoid arthritis. Given that fibrin (ogen), plasmin(ogen), fibrin degradation products (FDPs), and their cell surface receptors have been shown to be important in both the inflammatory response and tissue remodeling/repair, hemostasis-related proteins are prime candidates to be critical determinants of inflammatory joint disease. The aims of this project center on the following specific hypotheses: 1) fibrin (ogen) and plasmin-mediated proteolysis are important in the inflammatory processes leading to the synovial remodeling, pannus formation, neovascularization, cartilage destruction and bone erosion; 2) the mechanism by which fibrinogen contributes to the inopportune inflammatory and synovial cell activity leading progressive joint degeneration is coupled to: i) the local formation of provisional fibrin matrices, and ii) the local cellular engagement of fibrin(ogen) through specific integrin receptors; and 3) thrombin, the enzyme that proteolytically converts fibrinogen to fibrin, contributes to inflammatory joint disease through both fibrinogen-dependent and fibrinogen-independent mechanisms. These hypotheses will be tested by exploring the impact of genetic deficits and functional disorders in fibrinogen, plasminogen, and plasminogen activators on cytokine-driven and adaptive immunity-driven arthritis induced by either TNF-alpha transgene expression (Aim 1A) or immunization with type II collagen (Aim 1B). The specific importance of fibrinogen engagement of leukocyte and platelet integrin receptors in arthritis will be defined by comparative studies of arthritis in mice expressing mutant forms of fibrinogen lacking either the alpha-M-Beta-2 or alpha-IIb-beta-3 integrin binding motifs (Aim 2). Similarly, the importance of local thrombin-mediated conversion of fibrinogen to insoluble fibrin matrices in the pathogenesis of inflammatory joint disease will be defined in mice where thrombin activity is pharmacologically and/or genetically blocked (Aim 3). The proposed studies will provide a more detailed understanding of the role of hemostatic factors in the pathogenesis of arthritic disease with distinct etiologies, and could ultimately illuminate new therapeutic strategies for treating joint disease.

描述（由申请人提供）：该研究计划的长期目标是了解关键止血因素在炎症性关节疾病中的作用。关节内纤维蛋白（OGEN）和纤维蛋白降解产物的广泛沉积是类风湿关节炎的最明显特征之一。鉴于纤维蛋白（OGEN），纤溶酶（OGEN），纤维蛋白降解产物（FDP）及其细胞表面受体在炎症反应和组织重塑/修复中都很重要，因此与止血相关的蛋白质是主要候选者炎症性关节疾病的关键决定因素。该项目中心在以下特定假设上的目的：1）纤维蛋白（OGEN）和纤溶酶介导的蛋白水解在导致滑膜重塑，Pannus形成，新血管形成，软骨破坏和骨腐蚀的炎症过程中很重要； 2）纤维蛋白原有助于不合时宜的炎症和滑膜细胞活性，导致进行性关节变性的耦合到：i）临时纤维蛋白基质的局部形成，ii）纤维蛋白（OGEN）通过特定的整合素受体的局部细胞参与; 3）凝血酶，蛋白水解将纤维蛋白原转化为纤维蛋白的酶通过纤维蛋白原依赖性和与纤维蛋白原无关的机制有助于炎性关节疾病。这些假设将通过探索遗传缺陷和功能障碍在纤维蛋白原，纤溶酶原和纤溶酶原激活剂对细胞因子驱动和适应性免疫驱动的关节炎对TNF-ALPHA转基因表达（AIM 1A）或II型II型TNF-ALPHA诱导的关节炎的影响（AIM 1A）或适应性免疫驱动的关节炎。胶原蛋白（AIM 1B）。白细胞和血小板整联蛋白受体在关节炎中的纤维蛋白原参与度的具体重要性将通过对表达缺乏Alpha-M-Beta-2或Alpha-IIB-IIB-IIB-BETA-BETA-BETA-BETA-BETA-BETA的突变形式的关节炎进行比较研究来定义（目标2）。同样，将在凝血酶活性在药理学和/或遗传上阻塞的小鼠中定义局部凝血酶介导的纤维蛋白原转化为炎性关节疾病发病机理中不溶性纤维蛋白基质的重要性（AIM 3）。拟议的研究将对止血因素在具有不同病因的关节炎发病机理中的作用提供更详细的了解，并最终可以阐明治疗关节疾病的新治疗策略。