Hemostatic factors and sickle cell disease

止血因素和镰状细胞病

基本信息

批准号：
8585089
负责人：
JAY L DEGEN
金额：
$ 37.49万
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/8585089
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

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.

概括该研究计划的长期目标是定义中心止血的机制蛋白酶，凝血酶有助于镰状细胞疾病（SCD）病理的发展。开创性的角色止血和血管生物学中的凝血酶的蛋白酶积极控制的事实强调了纤维蛋白沉积，血小板激活和内皮细胞（EC）信号传导事件通过多个底物和受体[例如蛋白酶激活的受体，纤维蛋白原，因子XI和因子XIII]，以及负面通过激活蛋白C的激活来控制进一步的凝血酶，一种天然抗凝剂，已知抗炎/细胞保护特性。凝血酶活性的控制已深入研究因为凝血酶介导的蛋白水解是生理止血和病理学的基础血管熟悉的事件，包括心肌梗塞，静脉血栓形成和中风。但是，另一个用于凝血酶和凝血酶靶标的详细研究的驱动力是这些蛋白还控制血管渗透性/屏障功能，组织修复和炎症，共同发展多种炎症性疾病。鉴于循环镰状细胞导致血管损伤的组合，闭塞事件和炎症变化，鉴于局部和全身性止血系统的激活是 SCD，凝血酶和凝血酶靶标的显着特征是临床上重要的候选者镰状细胞病理生物学的修饰符。该项目中心的目的是两个一般假设：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的主要调节剂过程是SCD病理的主要决定因素，ii）可以改善与SCD相关的病态通过新的遗传或药理学干预措施在蛋白/凝血酶和下游凝血酶的水平上进行基材。这些假设将通过研究的重点来确定的重要性来检验凝血酶素在多器官SCD病理和伯克利镰状小鼠的长期生存中的发展中（HBA0/HBB0 [TG（HUMEN HBS）]+/+）（AIM 1）;了解凝血酶介导的纤维蛋白（OGE）依赖性和纤维蛋白（OGEN）独立的机制驱动SCD病理学（AIM 2）；并建立潜在利益在限制小鼠的SCD病理学方面，凝血酶靶向的药理学干预（AIM 3）。提议研究将首次清楚地了解止血因素在 SCD和SCD的发病机理可能会阐明新型的治疗策略，以限制SCD引起的病因。