Impaired Collateral Vessel Formation in Sickle Cell Disease

镰状细胞病中侧支血管形成受损

• 批准号: 9751364
• 负责人: DAVID R ARCHER
• 金额: $ 60.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751364
• 关键词: Address; Anatomy; Beds; Blood; Blood Vessels; Blood flow; Bone Marrow Transplantation; Clinical; Coronary Arteriosclerosis; Data; Defect; Development; Disease; Distal; Equilibrium; Evaluation; Excision; Generations; Heme; Hemoglobin; Hemolysis; Human body; Hydrogen Peroxide; Impairment; Inflammation; Inflammatory; Inflammatory Response; Ischemia; Kidney Failure; Limb structure; Modeling; Molecular; Morbidity - disease rate; Mus; Obstruction; Oxidative Stress; Pain; Pathologic; Pathology; Perfusion; Peripheral Vascular Diseases; Pharmacology; Physiological; Process; Production; Proteins; Reactive Oxygen Species; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Site; Stroke; TLR4 gene; Testing; Tissues; base; femoral artery; genetic approach; insight; mortality; mouse model; novel therapeutics; response; sickle cell crisis; vascular bed

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.

项目摘要 镰状细胞病的部分特征是由于血管闭塞而反复发作组织缺血。 镰状细胞病的大多数并发症，包括中风、疼痛危象、肾功能衰竭等，都可以归因于 这些血管功能不全的发作。人体的正常适应性反应 血管闭塞是指侧支血管的形成，以允许血管床远端的灌流 到达障碍物的位置。其他疾病，如冠状动脉疾病和外周血管疾病 疾病、侧支循环功能障碍与发病率和死亡率的增加有关。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 这种疾病的终极病理的许多方面。本申请中建议的研究包括 基于共同PI产生的令人兴奋的初步数据显示，在镰刀鼠模型中 细胞性疾病，侧支血管形成显著受损，病理的一个标志是 对缺血的不适应反应，导致过度炎症和过度产生反应性 氧气物种。我们将尝试对功能失调的侧支血管有更多的了解 镰状细胞病的形成，更重要的是，获得对潜在病理的洞察 机制，以便为新的治疗策略奠定基础。 我们的总体假设是，镰状细胞病的侧支血管形成受到损害，因为 由过量生产引起的不成比例的炎症反应的结果 活性氧物种。

项目成果

Increasing nitric oxide bioavailability fails to improve collateral vessel formation in humanized sickle cell mice.

• DOI: 10.1038/s41374-022-00780-0
• 发表时间: 2022-08
• 期刊: LABORATORY INVESTIGATION
• 影响因子: 5
• 作者: Lewis, Caitlin, V;Sellak, Hassan;Hansen, Laura;Joseph, Giji;Hurtado, Julian;Archer, David R.;Jun, Ho-Wook;Brown, Lou Ann;Taylor, W. Robert
• 通讯作者: Taylor, W. Robert