Vitamin B6, Vascular Dysfunction and Adhesion Molecules in Sickle Cell Disease

镰状细胞病中的维生素 B6、血管功能障碍和粘附分子

• 批准号: 7263763
• 负责人: RALPH GREEN
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263763
• 关键词: Accounting; Acute; Adhesions; Adult; Affect; Age; Aging; Anemia; Basic Science; Biological Assay; Blood; Blood Flow Velocity; Blood Platelets; Blood Vessels; Blood flow; Caliber; Cardiovascular Diseases; Cell Adhesion Molecules; Cerebral Infarction; Characteristics; Child; Childhood; Chronic; Clinical; Computer Assisted; Condition; Daily; Data; Dietary Intervention; Disease; Doctor of Philosophy; Double-Blind Method; Dysmorphology; Erythrocytes; Event; Eye; Functional disorder; Future; General Population; Goals; Head; Health; Heart; Hemolysis; High Prevalence; Injury; Intervention; Invasive; Kidney; Kidney Diseases; Laboratories; Leukocytes; Lung; Measurement; Measures; Mediating; Medical Research; Microcirculation; Minority; Morbidity - disease rate; Morphology; Occlusion injury; Outcome Measure; Pain; Pathogenesis; Patients; Peripheral Vascular Diseases; Physicians; Placebos; Plasma; Play; Population; Priapism; Protocols documentation; Pyridoxal Phosphate; Quality of life; Range; Recruitment Activity; Renal Hypertension; Research; Research Design; Research Personnel; Risk; Risk Factors; Role; Scientist; Severities; Sickle Cell; Sickle Cell Anemia; Spleen; Standards of Weights and Measures; Stroke; Supplementation; Techniques; Testing; Time; Training; Translations; United States National Institutes of Health; Vascular Diseases; Vascular Endothelium; Vitamin B 6 Deficiency; Vitamin B6; Vitamins; acute chest syndrome; bulbar conjunctiva; cost; cytokine; day; improved; in vivo; innovative technologies; intravital microscopy; morphometry; mortality; placebo controlled study

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is characterized by acute clinical manifestations, including painful crisis, acute chest syndrome, priapism, and stroke, as well as chronic irreversible damage to the heart, lungs, kidneys, eyes, spleen and femoral heads. Vascular injury and occlusion, primarily affecting the microvasculature, underlie most of these complications. Another characteristic of sickle cell patients, both adult and pediatric, is a high prevalence of low vitamin B6 status (exceeding 50%), as indicated by low plasma pyridoxal-5'- phosphate levels (<20 nmol/L). B6 deficiency is a risk factor for cardiovascular disease, peripheral vascular disease, and stroke in the general population, but it is unknown if low B6 status affects vascular morbidity in SCD patients. Preliminary data from our laboratory indicate that low B6 status is associated with increased circulating levels of adhesion molecules that mediate erythrocyte and leukocyte adhesion to the vascular endothelium, key events in the pathogenesis of vascular occlusion in SCD patients. Accordingly, the long- term objective of this proposal is to test the hypothesis that B6 supplements in SCD patients will reduce levels of adhesion molecules and improve vascular function. The specific aims are 1) to assess the cross- sectional relationships between B6 status, vascular adhesion molecules, and microvascular morphology and function in SCD patients, and 2) to assess the effect of B6 supplements on these parameters in the same patients. Adult and pediatric SCD patients, characterized using standard hematological measurements, will be assessed at baseline for blood levels of pyridoxal-5'-phosphate, soluble adhesion molecules known to be related to vascular injury (by real-time multiplex assay), and blood flow velocity and microvessel morphometry (by direct real-time computer-assisted intravital microscopy). To test the hypothesis that B6 supplements will result in improved microvascular morphometry and blood flow associated with a decrease in levels of circulating adhesion molecules, these patients will be treated for one year with vitamin B6 supplements using a double-blind, placebo-controlled study design. Repeat measurements of B6 status, levels of adhesion molecules and microvascular characteristics will be carried out at three-month intervals during the period of intervention. The vascular complications of SCD have a major negative impact on morbidity, mortality, and quality of life for these patients. The positive health impact of vitamin supplementation that could ameliorate the high morbidity and mortality associated with this disorder has the potential for high benefit with minimal cost and risk.

描述（由申请人提供）：镰状细胞病（SCD）的特征是急性临床表现，包括疼痛危象、急性胸部综合征、阴茎异常勃起和中风，以及对心脏、肺、肾、眼、脾和股骨头的慢性不可逆损伤。血管损伤和闭塞，主要影响微血管，是大多数这些并发症的基础。镰状细胞患者的另一个特征，无论是成人还是儿童，是低维生素B6状态的高患病率（超过50%），如低血浆吡哆醛-5 '-磷酸水平（<20 nmol/L）所示。在一般人群中，B6缺乏是心血管疾病、外周血管疾病和卒中的危险因素，但B6水平低是否会影响SCD患者的血管发病率尚不清楚。我们实验室的初步数据表明，低B6状态与介导红细胞和白细胞粘附于血管内皮的粘附分子的循环水平增加有关，这是SCD患者血管闭塞发病机制中的关键事件。因此，本提案的长期目标是检验SCD患者中B6补充剂将降低粘附分子水平并改善血管功能的假设。具体目的是：1）评估SCD患者中B6状态、血管粘附分子和微血管形态和功能之间的横截面关系; 2）评估B6补充剂对相同患者中这些参数的影响。将在基线时评估成人和儿童SCD患者（使用标准血液学测量进行表征）的吡哆醛-5 '-磷酸盐、已知与血管损伤相关的可溶性粘附分子（通过实时多重测定）以及血流速度和微血管形态测定（通过直接实时计算机辅助活体显微镜检查）的血液水平。为了检验B6补充剂将导致与循环粘附分子水平降低相关的微血管形态学和血流改善的假设，这些患者将使用双盲、安慰剂对照研究设计用维生素B6补充剂治疗一年。在干预期间，将每隔三个月重复测量B6状态、粘附分子水平和微血管特征。SCD的血管并发症对这些患者的发病率、死亡率和生活质量具有重大的负面影响。维生素补充剂对健康的积极影响可以改善与这种疾病相关的高发病率和死亡率，有可能以最小的成本和风险获得高效益。