Erythrocyte Nitric Oxide Links Rheology and Vasculopathy in Sickle Cell Disease

红细胞一氧化氮与镰状细胞病的流变学和血管病变有关

• 批准号: 8768241
• 负责人: Jon A Detterich
• 金额: $ 15.76万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2017-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768241
• 关键词: Abnormal Red Blood Cell; Acute; Adenosine Triphosphate; Affect; Arginine; Binding; Bioavailable; Biochemical; Biological Availability; Blood; Blood Vessels; Cardiology; Cell membrane; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Complex; Disease; Endothelium; Enzymes; Erythrocytes; Generations; Grant; Heart; Hematology; Heme; Hemoglobin; Hemolysis; Hyperemia; Hypoxia; In Vitro; Individual; Knowledge; Laboratories; Lead; Link; Measurement; Measures; Mechanics; Mediating; Mediator of activation protein; Membrane; Mentored Patient-Oriented Research Career Development Award; Methods; Morbidity - disease rate; Mutation; NADH; NADP; Near-Infrared Spectroscopy; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Oxidative Stress; Oxygen; Oxygen measurement, partial pressure, arterial; Pain; Patient Care; Patients; Phosphorylation; Platelet aggregation; Play; Preparation; Process; Production; Property; Pulmonary Hypertension; Rattus; Reperfusion Injury; Research Proposals; Research Training; Rheology; Role; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Skin Ulcer; Stress; Stroke; Testing; Translating; United States; Vascular Diseases; Vascular Endothelium; Vascular System; Vascular remodeling; Vasodilation; Work; acute chest syndrome; arginase; base; career development; cell injury; cost; human NOS3 protein; improved; insight; mortality; new therapeutic target; novel; patient oriented research; premature; prevent; public health relevance; shear stress; stem; tetrahydrobiopterin; tissue oxygenation; translational study; vascular bed

DESCRIPTION (provided by applicant): Sickle cell disease is a progressive vasculopathy stemming from decreased red blood cell (RBC) deformability. Vascular disease is at the heart of both acute and chronic sickle disease, including pain crisis, acute chest syndrome, stroke, skin ulcers, and pulmonary hypertension. However, the mechanisms linking decreased RBC deformability to chronic vasculopathy are multifactorial and poorly characterized. Nitric oxide (NO) is the key mediator linking blood mechanics to vessel tone and vascular remodeling. As bloodflow shears the endothelium, NO is released, causing vasodilation and inhibiting platelet aggregation. NO bioavailability is diminished in SCD because decellularized hemoglobin and arginase, released during hemolysis, scavenge NO and lower endothelial NO production. Recent evidence suggests that 50% of bioavailable NO is synthesized within RBC, themselves, though a shear-activated eNOS enzyme. RBC NO is primarily converted to nitrite and nitrosylated hemoglobins when tissue oxygenation is high, but deoxygenated hemoglobin converts these species to nitric oxide under hypoxic conductions. Thus, RBC generated NO appears to be a vital mediator of oxygen supply and demand and its role in sickle cell vasculopathy is completely unexplored. Our fundamental hypothesis is that decreased red cell deformability reduces shear-mediated nitric oxide production by the red cell itself, crippling vita "storage" forms of nitric oxide, causing vascular dysfunction at several levels of the vascular system. This research proposal merges novel laboratory methods in RBC nitric oxide production with clinical investigation of vascular dysfunction in patients with sickle cell disease Multimodal characterization of the different vascular beds will lead to improved phenotypic categorization and pathophysiological links to the underlying RBC biophysical/biochemical derangements. We will also explore whether RBC-generated NO has the ability to directly affect the vasculature using aortic ring preps and whether RBC-generated NO decreases platelet aggregation. Support from this grant benefits SCD patients in three ways: 1) it improves cross- specialization (i.e. hematology and cardiology), 2) it translates novel lab based methods in RBC generation of NO to patients using vascular preps and measurement of platelet aggregation, and 3) it will set the ground work for larger clinical translational studies linking RBC-generated NO and rheology with sophisticated measures of vascular function in patients with SCD. The K23 mechanism represents the natural extension my career development to date, combining my previous laboratory and patient-oriented research expertise with the specific clinical research training necessary to conduct large translational studies of novel targets in vascular dysfunction.

描述（由申请人提供）：镰状细胞病是一种进行性血管病，源于红细胞（RBC）变形能力降低。血管疾病是急性和慢性镰状病的核心，包括疼痛危象、急性胸部综合征、中风、皮肤溃疡和肺动脉高压。然而，红细胞变形性降低与慢性血管病变的联系机制是多因素的，且特征不明确。一氧化氮（NO）是连接血液力学与血管张力和血管重塑的关键介质。当血流剪切内皮时，NO被释放，引起血管舒张并抑制血小板聚集。SCD患者NO的生物利用度降低，因为脱细胞血红蛋白和脱细胞酶在溶血过程中释放，导致NO减少和内皮NO产生减少。最近的证据表明，50%的生物可利用的NO是在红细胞内合成的，通过剪切激活的eNOS酶。当组织氧合高时，RBC NO主要转化为亚硝酸盐和亚硝基化血红蛋白，但脱氧血红蛋白在缺氧传导下将这些物质转化为一氧化氮。因此，RBC产生的NO似乎是氧供应和需求的重要介质，其在镰状细胞血管病变中的作用完全未被探索。 我们的基本假设是，降低红细胞变形能力减少了红细胞本身的剪切介导的一氧化氮产生，削弱了一氧化氮的维生素“储存”形式，导致血管系统的几个层次的血管功能障碍。 这项研究建议合并新的实验室方法在红细胞一氧化氮生产与临床调查的血管功能障碍的镰状细胞病患者的多模式表征不同的血管床将导致改善表型分类和病理生理学联系的基础红细胞生物物理/生化紊乱。我们还将探索RBC产生的NO是否具有使用主动脉环制备物直接影响脉管系统的能力，以及RBC产生的NO是否降低血小板聚集。这项补助金的支持使SCD患者在三个方面受益：1）它促进了交叉专业化（即血液学和心脏病学），2）它将基于实验室的新方法转化为使用血管制备和血小板聚集测量的患者的RBC产生NO，和3）它将为更大的临床转化研究奠定基础，在SCD患者中，通过复杂的血管功能测量来产生NO和流变学。 K23机制代表了我迄今为止职业发展的自然延伸，将我以前的实验室和以患者为导向的研究专业知识与进行血管功能障碍新靶点的大型转化研究所需的特定临床研究培训相结合。