Arthritic Disease and the Hemostatic System

描述（由申请人提供）：本研究项目的长期目标是了解炎性关节疾病中关键止血因子的作用。纤维蛋白（原）和纤维蛋白降解产物在关节内的广泛沉积是类风湿关节炎最显著的特征之一。鉴于纤维蛋白（原）、纤溶蛋白（原）、纤维蛋白降解产物（fdp）及其细胞表面受体已被证明在炎症反应和组织重塑/修复中都很重要，止血相关蛋白是炎症性关节疾病关键决定因素的主要候选蛋白。本项目的目标集中在以下具体假设上：1)纤维蛋白（原）和纤溶蛋白介导的蛋白水解在导致滑膜重塑、滑膜形成、新生血管形成、软骨破坏和骨侵蚀的炎症过程中很重要；2)纤维蛋白原促进不合时宜的炎症和滑膜细胞活性导致进行性关节变性的机制与：1)临时纤维蛋白基质的局部形成，以及ii)纤维蛋白（原）通过特异性整合素受体局部参与细胞；3)凝血酶，一种将纤维蛋白原转化为纤维蛋白的酶，通过纤维蛋白原依赖和纤维蛋白原独立的机制参与炎症性关节疾病。这些假设将通过探索纤维蛋白原、纤溶酶原和纤溶酶原激活剂的遗传缺陷和功能障碍对细胞因子驱动和适应性免疫驱动关节炎的影响来验证，这些关节炎是由tnf - α转基因表达（Aim 1A）或II型胶原免疫（Aim 1B）诱导的。纤维蛋白原结合白细胞和血小板整合素受体在关节炎中的特殊重要性将通过对表达缺乏α - m - β -2或α - iib - β -3整合素结合基序的纤维蛋白原突变形式的小鼠关节炎的比较研究来确定（目的2）。同样，局部凝血酶介导的纤维蛋白原向不溶性纤维蛋白基质转化在炎性关节疾病发病机制中的重要性将在凝血酶活性被药理学和/或遗传阻断的小鼠中确定（目的3）。所提出的研究将提供更详细的了解止血因子在具有不同病因的关节炎发病机制中的作用，并可能最终阐明治疗关节疾病的新治疗策略。

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.