Impaired Collateral Vessel Formation in Sickle Cell Disease

项目摘要 镰状细胞病的部分特征是由于血管闭塞引起的组织缺血的反复发作。 大多数镰状细胞病的并发症包括中风、疼痛危象、肾衰竭等都可以归因于 血管功能不全的症状一种正常的人体适应性反应， 血管闭塞是侧支血管的发展，以允许远端血管床的灌注 到梗阻部位。在其他疾病如冠状动脉疾病和外周血管疾病中， 疾病时，侧支血流功能障碍与发病率和死亡率增加有关。我们有 假设在镰状细胞病中，功能障碍的侧支血管的形成与 疾病的最终病理学的许多方面。本申请中提出的研究是 基于co-PI产生的令人兴奋的初步数据，这些数据显示，在镰状细胞的小鼠模型中， 细胞疾病时，侧支血管形成显著受损，并且病理学的标志是 对局部缺血的适应不良反应，导致过度炎症和反应性 氧物种。我们将尝试更深入地了解功能失调的侧支血管 镰状细胞病的形成，更重要的是， 机制，以便为新的治疗策略奠定基础。 我们的总体假设是，镰状细胞病侧支血管形成受损， 由于过度产生的不成比例的炎症反应， 活性氧

PROJECT ABSTRACT Sickle cell disease is characterized in part by repeated bouts of tissue ischemia due to vascular occlusion. Most of the complications of sickle cell disease including stroke, pain crises, renal failure, etc. can be attributed to these episodes of vascular insufficiency. A normal adaptive response of the human body to vascular occlusion is the development of collateral blood vessels to allow perfusion of the vascular bed distal to the site of obstruction. In other diseases such as coronary artery disease and peripheral vascular disease, dysfunctional collateral blood flow is associated with increased morbidity and mortality. We have hypothesized that in sickle cell disease, formation of dysfunctional collateral blood vessels is directly related to many aspects of the ultimate pathology of the disease. The studies proposed in this application are based on exciting preliminary data generated by the co-PI’s that show that in a murine model of sickle cell disease, collateral vessel formation is dramatically impaired and that a hallmark of the pathology is a maladaptive response to ischemia that results in excessive inflammation and overproduction of reactive oxygen species. We will attempt to gain a greater understanding of dysfunctional collateral vessel formation in sickle cell disease and more importantly, obtain insights into the underlying pathological mechanisms in order to lay the groundwork for novel therapeutic strategies. Our overall hypothesis is that collateral vessel formation in sickle cell disease is impaired as the result of a disproportionate inflammatory response driven by the excessive production of reactive oxygen species.