Hemostatic factors and sickle cell disease

止血因素和镰状细胞病

• 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
• 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

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）：本研究项目的长期目标是确定中央止血蛋白酶，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重要作用是通过多种底物和受体（如蛋白酶激活受体、纤维蛋白原、因子XI和因子XIII）积极控制纤维蛋白沉积、血小板活化和内皮细胞（EC）信号事件，以及通过蛋白质活化进一步控制凝血酶的产生，这一事实强调了凝血酶的重要性