Hemostatic factors and sickle cell disease

总结 这项研究计划的长期目标是确定中央止血的机制， 蛋白酶凝血酶有助于镰状细胞病（SCD）病理学的发展。开创性作用 凝血酶在止血和血管生物学中的重要作用，强调了这种蛋白酶积极控制 纤维蛋白沉积、血小板活化和内皮细胞（EC）信号传导事件， 受体[例如，蛋白酶激活受体、纤维蛋白原、因子Xi和因子XIII]，以及负性 通过蛋白C的活化进一步控制凝血酶的产生，蛋白C是一种天然抗凝血剂， 抗炎/细胞保护特性。凝血酶活性的控制已被深入研究 因为凝血酶介导的蛋白水解是生理止血和病理止血的基础， 血管闭塞事件，包括心肌梗死、静脉血栓形成和卒中。然而，一个额外的 对凝血酶和凝血酶靶点进行详细研究的驱动力是这些蛋白质也控制血管生成， 渗透性/屏障功能，组织修复和炎症，这些共同促进了 多种炎症性疾病。鉴于循环镰状细胞导致血管损伤， 闭塞事件和炎症变化，并且考虑到局部和全身止血系统激活是 SCD的一个显著特征是凝血酶和凝血酶靶点是具有临床意义的主要候选者 镰状细胞病病理生物学的修饰剂。本项目的目标集中在两个一般假设：i） 凝血酶作为血管生物学、血小板/EC活化、纤维蛋白沉积和炎症的主要调节剂， 过程，是SCD病理的主要决定因素，和ii）SCD相关的发病率可以改善 通过在凝血酶原和下游凝血酶水平上的新型遗传或药理学干预， 印刷受体.这些假设将通过重点定义以下重要性的研究来检验 凝血酶原在Berkeley镰状小鼠多器官SCD病理和长期存活中的作用 (Hba0/Hbb 0 [Tg（人HbS）]+/+）（目的1）;了解凝血酶介导的、纤维蛋白（原）依赖的和 驱动SCD病理的纤维蛋白（原）非依赖性机制（目的2）;并确定潜在获益 凝血酶靶向药物干预限制小鼠SCD病理（目的3）。拟议 研究将首次提供对止血因子在治疗中的重要性的清晰理解。 SCD的发病机制，并可能阐明新的治疗策略，以限制SCD诱导的发病率。

SUMMARY The long-term objective of this research program is to define the mechanisms by which the central hemostatic protease, thrombin, contributes to the development of sickle cell disease (SCD) pathologies. The seminal role of thrombin in hemostasis and vascular biology is underscored by the fact that this protease positively controls fibrin deposition, platelet activation, and endothelial cell (EC) signaling events via multiple substrates and receptors [e.g., protease-activated receptors, fibrinogen, factor XI, and factor XIII], as well as negatively controls further thrombin generation through the activation of protein C, a natural anticoagulant with known anti-inflammatory/cytoprotective properties. The control of thrombin activity has been intensely studied because thrombin-mediated proteolysis is fundamental to both physiological hemostasis and pathological vaso-occlusive events, including myocardial infarction, venous thrombosis and stroke. However, an additional driving force for detailed studies of thrombin and thrombin targets is that these proteins also control vascular permeability/barrier function, tissue repair, and inflammation, which together contribute to the development of multiple inflammatory diseases. Given that circulating sickle cells result in a combination of vascular damage, occlusive events and inflammatory changes, and given that local and systemic hemostatic system activation is a conspicuous feature of SCD, thrombin and thrombin targets are prime candidates to be clinically-significant modifiers of sickle cell disease pathobiology. The aims of this project center on two general hypotheses: i) thrombin, as a master regulator of vascular biology, platelet/EC activation, fibrin deposition and inflammatory processes, is a major determinant of SCD pathologies, and ii) SCD-associated morbidities can be ameliorated by novel genetic or pharmacological interventions at the level of pro/thrombin and downstream thrombin substrates. These hypotheses will be tested through studies that focus on defining the importance of prothrombin in the development of multi-organ SCD pathologies and long-term survival in Berkeley sickle mice (Hba0/Hbb0 [Tg(Human HbS)]+/+) (Aim 1); understanding the thrombin-mediated, fibrin(ogen)-dependent and fibrin(ogen)-independent mechanisms driving SCD pathologies (Aim 2); and establishing the potential benefit of thrombin-targeted pharmacological intervention in limiting SCD pathologies in mice (Aim 3). The proposed studies will provide for the first time a clear understanding of the significance of hemostatic factors in the pathogenesis of SCD and may illuminate novel therapeutic strategies for limiting SCD-induced morbidities.