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 镰状细胞疾病的特征是由于血管阻塞引起的组织缺血的反复发作。 镰状细胞疾病的大多数并发症包括中风，疼痛危机，肾衰竭等 这些血管功能不全的发作。人体对 血管阻塞是副血管的发展，以使血管床灌注不同 到反对地点。在其他疾病中，例如冠状动脉疾病和周围血管 疾病，功能失调的附带血流与发病率和死亡率增加有关。我们有 假设在镰状细胞疾病中，功能失调的附带血管的形成与 疾病最终病理的许多方面。该应用中提出的研究是 基于Co-Pi产生的激动人心的初步数据，该数据表明在镰状的鼠模型中 细胞疾病，副血管形成严重受损，病理的标志是 对缺血的适应不良反应，导致过度炎症和反应性过多 氧。我们将尝试更了解功能失调的侧支容器 镰状细胞疾病的形成，更重要的是，获得对潜在病理学的见解 为了为新颖的治疗策略奠定基础机制。 我们的总体假设是，镰状细胞疾病中的附带血管形成被损害 过量产生驱动的炎症反应不成比例的结果 活性氧。

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