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关键止血因子在炎症性关节疾病中的作用。关节内纤维蛋白（原）和纤维蛋白降解产物的广泛沉积是类风湿性关节炎最显著的特征之一。鉴于纤维蛋白（原）、纤溶酶（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/修复中均很重要，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者。本项目的目的集中于以下特定假设：1）纤维蛋白（原）和纤溶酶介导的蛋白水解在导致滑膜重塑、血管翳形成、新血管形成、软骨破坏和骨侵蚀的炎症过程中很重要; 2）纤维蛋白原导致不合时宜的炎症和滑膜细胞活动导致进行性关节退行性变的机制与以下因素相关：i）临时纤维蛋白基质的局部形成，和ii）通过特异性整联蛋白受体的纤维蛋白（原）的局部细胞接合;和3）凝血酶，将纤维蛋白原蛋白水解转化为纤维蛋白的酶，通过纤维蛋白原依赖性和纤维蛋白原非依赖性机制促成炎性关节疾病。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TNF-α转基因表达（Aim 1A）或II型胶原免疫（Aim 1B）诱导的精氨酸驱动和适应性免疫驱动关节炎的影响进行检验。白细胞和血小板整联蛋白受体的纤维蛋白原参与关节炎的特殊重要性将通过表达缺乏α-M-β-2或α-IIb-β-3整联蛋白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）。类似地，将在凝血酶活性被抑制和/或遗传阻断的小鼠中确定局部凝血酶介导的纤维蛋白原转化为不溶性纤维蛋白基质在炎性关节疾病发病机制中的重要性（目的3）。拟议的研究将提供一个更详细的了解止血因子的作用，在关节炎疾病的发病机制与不同的病因，并最终阐明新的治疗策略，治疗关节疾病。

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.