Hemostatic factors and sickle cell disease

描述（由申请方提供）：本研究项目的长期目标是确定中心止血蛋白酶凝血酶促进镰状细胞病（SCD）病理发展的机制。凝血酶在止血和血管生物学中的开创性作用通过以下事实强调：该蛋白酶通过多种底物和受体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[例如，蛋白酶激活受体、纤维蛋白原、因子Xi和因子XIII]，以及通过蛋白质的激活负控制进一步的凝血酶生成 C，一种天然抗凝剂，具有已知的抗炎/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性止血和病理性血管闭塞事件（包括心肌梗死、静脉血栓形成和中风）的基础。然而，对凝血酶和凝血酶靶点进行详细研究的另一个驱动力是，这些蛋白质还控制血管通透性/屏障功能、组织修复和炎症，它们共同促进多种炎性疾病的发展。考虑到循环镰状细胞导致血管损伤、闭塞事件和炎症变化的组合，并且考虑到局部和全身止血系统激活是SCD的显著特征，凝血酶和凝血酶靶点是镰状细胞病的临床显著修饰剂的主要候选者 病理生物学该项目的目的集中在两个一般假设上：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过程的主要调节剂，是SCD病理的主要决定因素，和ii）SCD相关的发病率可以通过在凝血酶原/凝血酶和下游凝血酶底物水平的新型遗传或药理学干预来改善。这些假设将通过研究进行检验，这些研究的重点是确定凝血酶原在伯克利镰状小鼠多器官SCD病理学发展和长期生存中的重要性。（Hba 0/Hbb 0 [Tg（人HbS）]+/+））（目标1）;理解驱动SCD病理的凝血酶介导的、纤维蛋白（原）依赖的和纤维蛋白（原）非依赖的机制（目标2）;以及确定凝血酶靶向药物干预在限制小鼠SCD病理中的潜在益处（目的3）。拟议的研究将首次明确了解止血因子在SCD发病机制中的重要性，并可能阐明限制SCD诱导的发病率的新治疗策略。 公共卫生相关性：镰状细胞性贫血影响超过100，000名美国人和全球数百万人，并导致血管闭塞，疼痛危机，炎症，多器官损伤，中风和预期寿命缩短。有大量证据表明镰状细胞病患者凝血因子激活;然而，凝血因子对血管闭塞和炎症的确切作用仍不清楚。本研究的主要目标是利用现代分子遗传学来深入了解镰状细胞病中关键凝血因子的作用，并为患有这种疾病的患者探索新的治疗策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Sickle cell anemia affects over 100,000 Americans and millions worldwide and results in occlusion of blood vessels, pain crises, inflammation, damage to multiple organs, stroke and reduced life-expectancy. There is substantial evidence of coagulation ('clotting') factor activation in sickle cell patients; however, the precise contributin of coagulation factors to vessel occlusion and inflammation remains unclear. The primary goal of this research is to use modern molecular genetics to develop an in-depth understanding of the contribution of key coagulation factors in sickle cell disease and explore novel treatment strategies for patients with this disease.