Mechanisms of Vaso-occlusion in Sickle Cell Disease

镰状细胞病的血管闭塞机制

• 批准号: 6902802
• 负责人: Cheryl A Hillery
• 金额: $ 35.03万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6902802
• 关键词: blood vessel occlusion; fibrin; genetically modified animals; hematopoietic stem cells; inflammation; laboratory mouse; pathologic process; sickle cell anemia; stem cell transplantation; thrombin; vascular endothelium

DESCRIPTION (provided by applicant): The major cause of morbidity and mortality in sickle cell disease (SCO) is tissue ischemia and infarction due to vascular occlusion that results in progressive organ damage. It is unclear whether the enhanced procoagulant or inflammatory activity observed in SCO directly contributes to the pathogenesis of sickle cell vaso-occlusive disease or merely reflects vascular injury caused by the sickle erythrocyte. We hypothesize that sickle erythrocytes initially injure the endothelium, inducing both a proinflammatory and procoagulant phenotype; we propose that the increased inflammation contributes to reversible vascular stasis while the coagulant pathway contributes to the complete stoppage of blood flow and tissue infarction. The strong interrelationships between the inflammatory and hemostatic pathways set up a vicious cycle that further propagates this process. Therefore, the Specific Aims for this project are to 1) Characterize the effects of thrombin generation and fibrin formation on the cycle of HbS-induced endothelial injury, inflammation and vascular congestion, 2) Define the role of the tissue factor pathway in the evolution of sickle cell-induced vascular pathology, and 3) Study the effect of modulation of the protein C/thrombomodulin pathway on the evolution of HbS-induced organ pathology. We will induce SCO into mice with genetic alterations of specific components of the coagulation and coagulant signaling pathways using hematopoietic stem cell transplantation and test the effect on measures of inflammation and endothelial injury. We will also examine the effect of pharmacologic and genetic anticoagulant therapy in SCO mice as well as hypoxia-reoxygenation-treated SCO mice. Finally, we will study the role of thrombosis and inflammation on sickle red cell adhesion in vivo. We anticipate that these studies will clarify the interrelated roles of the coagulation system, vascular injury and inflammation in the evolution of sickle cell-induced vascular pathology. Additionally, these studies will provide insights into the value of targeted anticoagulant/anti-inflammatory therapies for the treatment and prevention of SCD vascular pathology.

描述（由申请人提供）：镰状细胞疾病（SCO）发病和死亡率的主要原因是组织缺血和梗塞，导致血管闭塞导致渐进的器官损害。目前尚不清楚SCO中观察到的促凝剂或炎症活性的增强是否直接有助于镰状细胞血管 - 易裂疾病的发病机理，或仅反映由镰状红细胞引起的血管损伤。我们假设镰状红细胞最初会损害内皮，从而诱导促炎和促凝表型。我们建议增加的炎症会导致可逆的血管粪便，而凝结途径则有助于完全停止血液流量和组织梗塞。炎症和止血途径之间的强烈相互关系建立了一个恶性循环，进一步传播了这一过程。因此，该项目的具体目的是1）表征凝血酶产生和纤维蛋白形成对HBS引起的内皮损伤，炎症和血管充血周期的影响，2）定义组织因子途径在镰状细胞诱导的血管病理学的进化中的作用，以及研究型载体的作用，以及3）载体的作用。病理。我们将使用造血干细胞移植的凝结和凝血信号传导途径的特定成分的遗传改变诱导SCO，并测试对炎症和内皮损伤的影响的影响。我们还将检查药理学和遗传抗凝治疗对SCO小鼠以及缺氧抗氧化治疗的SCO小鼠的作用。最后，我们将研究血栓形成和炎症在体内镰状细胞粘附的作用。我们预计这些研究将阐明凝血系统，血管损伤和炎症在镰状细胞诱导的血管病理发展中的相互关联作用。此外，这些研究将提供有关靶向抗凝/抗炎疗法对SCD血管病理治疗和预防的靶向疗法的价值的见解。