Hemostatic factors and sickle cell disease

止血因素和镰状细胞病

基本信息

批准号：
8256975
负责人：
JAY L DEGEN
金额：
$ 38.25万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8256975
关键词：
Affect Alleles American Anti-Inflammatory Agents Anti-inflammatory Anticoagulants Antisense Oligonucleotides Automobile Driving Binding Biology Blood Coagulation Factor Blood Platelets Blood Vessels Coagulation Process Deposition Development Disease Endothelial Cells Event Factor XI Factor XIII Fibrin Fibrinogen Generations Genetic Goals Hemostatic Agents Hemostatic function Hepatic Human Inflammation Inflammatory Integrins Intervention Knock-out Leukocytes Life Expectancy Mediating Molecular Genetics Morbidity - disease rate Mus Myocardial Infarction Oral Organ PAR-1 Receptor Pain Pathogenesis Pathology Patients Peptide Hydrolases Pharmacia brand of estropipate Physiological Platelet Activation Play Process Property Protease Domain Protein C Proteinase-Activated Receptors Proteins Proteolysis Prothrombin Recombinants Research Role Seminal Sickle Cell Sickle Cell Anemia Signal Transduction Stroke System Testing Therapeutic Thrombin Time Variant Vascular Permeabilities Venous Thrombosis blood vessel occlusion clinically significant driving force hemoglobin A(0)improved in vivo inhibitor/antagonist mortality mutant novel novel therapeutics preclinical study programs receptor research study sickling tissue repair treatment strategy

项目摘要

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.

描述（由申请人提供）：该研究计划的长期目标是定义中枢性止血蛋白酶，凝血酶有助于镰状细胞疾病（SCD）病理的机制。凝血酶在止血和血管生物学中的开创性作用突显了以下事实：这种蛋白酶通过多种底物和受体[例如，蛋白酶激活的受体，纤维蛋白原，纤维蛋白原，因子，纤维蛋白酶，纤维蛋白酶，纤维蛋白酶，纤维蛋白酶，因子，血小板激活和血小板激活和内皮细胞（EC）信号事件（EC）信号传导事件。 XI和因子XIII]，以及通过蛋白质激活来控制进一步的凝血酶生成 C，一种具有已知抗炎/细胞保护特性的天然抗凝剂。由于凝血酶介导的蛋白水解对生理止血和病理血管骨化事件的基础，包括心肌梗塞，静脉血栓形成和中风，因此对凝血酶活性的控制已经进行了深入研究。但是，用于详细研究凝血酶和凝血酶靶标的额外驱动力是，这些蛋白质还控制血管通透性/屏障功能，组织修复和炎症，这共同有助于多种炎症性疾病的发展。鉴于循环镰状细胞会导致血管损伤，闭塞事件和炎症性变化的结合，并且鉴于局部和全身性止血系统激活是SCD，凝血酶和凝血酶目标的显着特征细胞疾病病理生物学。该项目集中在两个一般假设上的目的：i）凝血酶作为血管生物学，血小板/EC激活，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，ii）scd相关的病态可能性很大。通过新的遗传或药理干预措施在蛋白/凝血酶和下游凝血酶底物的水平上得到改善。这些假设将通过研究的重点进行检验，该研究侧重于定义凝血酶蛋白在伯克利镰刀小鼠（HBA0/HBB0 [TG（Human HBS）]+/+）中的多器官SCD病理和长期生存中的重要性。目标1）;了解凝血酶介导的纤维蛋白（OGEN）依赖性和纤维蛋白（OGEN）独立的机制驱动SCD病理学（AIM 2）；并确定靶向凝血酶的药理学干预措施在限制小鼠的SCD病理方面的潜在益处（AIM 3）。拟议的研究将首次提供对止血因素在SCD发病机理中的重要性的清晰了解，并可能阐明新型的治疗策略，以限制SCD诱导的病态。公共卫生相关性：镰状细胞贫血在全球范围内影响超过100,000名美国人和数百万美元，并导致血管，疼痛危机，炎症，对多个器官的损害，中风和预期寿命减少。有大量证据表明镰状细胞患者的凝结（“凝结”）因子激活。然而，凝血因子对血管阻塞和炎症的确切贡献尚不清楚。这项研究的主要目的是使用现代分子遗传学来深入了解镰状细胞疾病中关键凝血因子的贡献，并探索该疾病患者的新型治疗策略。