Standardized Monitoring of Cellular Adhesion to Improve Clinical Care in Sickle Cell Disease

细胞粘附的标准化监测可改善镰状细胞病的临床护理

• 批准号: 9279250
• 负责人: Umut A. Gurkan
• 金额: $ 39.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9279250
• 关键词: Abnormal Red Blood Cell; Adhesions; Adhesives; Adult; Age; Atlases; Biological Assay; Cell Adhesion; Cell membrane; Characteristics; Child; Childhood; Clinic; Clinical; Clinical Trials; Complex; Databases; Deoxygenated Sickle Hemoglobin; Development; Diabetes Mellitus; Drops; E-Selectin; Endothelial Cells; Erythrocytes; Evaluation; Event; Fibronectins; Functional disorder; Glucose; Goals; Hemolysis; Hypoxemia; Individual; Knowledge; Laminin; Leukocytes; Longitudinal Studies; Measurement; Measures; Microfluidics; Monitor; Morbidity - disease rate; Mutation; Nature; Neuropathy; Outcome; P-Selectin; Pain; Patients; Play; Population; Population Heterogeneity; Prevalence; Property; Recording of previous events; Role; Shapes; Sickle Cell Anemia; Sickle Hemoglobin; Standardization; Techniques; Testing; Therapeutic Intervention; Time; Transfusion; Whole Blood; cellular targeting; chronic pain; clinical care; clinical investigation; density; experience; experimental study; hydroxyurea; improved; individual patient; insight; mortality; novel; polymerization; response; sickling; therapeutic target; treatment response

PROJECT SUMMARY The sickle hemoglobin mutation afflicts millions of people worldwide and is associated with considerable morbidity and mortality. The pathophysiology of Sickle Cell Disease (SCD) is a consequence of abnormal deoxygenated sickle hemoglobin polymerization and its deleterious effects on Red Blood Cell (RBC) membrane, shape, density, deformability, and adhesion. The original powerful observation that sickle red cells show abnormal adhesion to endothelial cells has since been deepened and expanded to describe a complex pathophysiology in which abnormal white blood cell (WBC) adhesion also plays an important role. These studies led to clinical trial development utilizing targeted anti-adhesion therapy. Despite the remarkable insights about abnormal cellular adhesion in SCD that have been made, there remain gaps in knowledge about these complex adhesive interactions. There is no established `atlas' of abnormal adhesive events, examined longitudinally and in a standardized manner in a large heterogeneous population of SCD patients under a range of clinical circumstance and with and without treatment. Neither the topography of adhesive events for an individual patient, nor for the SCD population as a whole is known. Better knowledge of the nature and scope of abnormal adhesive events is critical to the goals of establishing associations with clinical outcomes and successfully identifying therapeutic targets in clinical trials. We have developed a novel microfluidic assay that allows rapid, preprocessing free, and standardized interrogation of RBC and WBC adhesion in whole blood. In our ongoing experiments, high levels of HbF are associated with lesser adhesion, while greater adhesion is associated with hemolysis. In preliminary longitudinal studies, we find that RBC adhesion drops with initiation of treatment, and that levels of adhesion are stable in stably treated patients. Given our preliminary findings, we hypothesize that, in SCD: (1) changes in RBC or WBC adhesion will reflect the subjects' clinical state and treatment response, and (2) that the adhesive profile will change with age, and will differ between children and adults during vaso-occlusive crises (VOCs). To test these hypotheses, we propose the following distinct but interrelated Specific Aims: Aim 1: To standardize the simultaneous baseline evaluation of multiple cellular adhesive properties in a large population of asymptomatic adults and children (at more than one center and longitudinally); Aim 2: To determine the change from baseline in cellular adhesive properties that are present during vaso-occlusive crises, and to analyze these in adult and pediatric populations; and Aim 3: To examine changes in cellular adhesive properties before and after therapeutic interventions, including transfusions, hydroxyurea, and targeted anti- adhesion therapy. Our studies will afford the more precise characterization of abnormal adhesive events in a given individual and a more accurate assessment of response to therapy overall. We would like to make adhesion testing as feasible, and clinically meaningful, in SCD as glucose testing is in diabetes.

项目摘要 镰状血红蛋白突变困扰着全世界数百万人，并与相当大的 发病率和死亡率。镰状细胞病（SCD）的病理生理学是一个异常的结果， 脱氧镰状血红蛋白聚合及其对红细胞的有害作用 膜、形状、密度、可变形性和粘附性。最初有力的观察表明镰状红细胞 显示对内皮细胞的异常粘附已经被深化和扩展，以描述一种复杂的 其中异常白色血细胞（WBC）粘附也起重要作用的病理生理学。这些 研究导致了利用靶向抗粘连疗法的临床试验开发。尽管有着非凡的洞察力 关于SCD中异常细胞粘附的研究已经取得了进展，关于这些知识仍然存在空白 复杂的粘附相互作用。没有建立异常粘连事件的“图谱”，检查 纵向和标准化的方式在一个大的异质性SCD患者群体下， 一系列的临床情况和治疗和不治疗。无论是粘附事件的地形， 单个患者，也不知道SCD人群作为一个整体。更好地了解自然， 异常粘连事件的范围对于建立与临床结局的关联至关重要 并在临床试验中成功确定治疗靶点。 我们已经开发了一种新的微流控检测，允许快速，预处理免费，和标准化 全血中红细胞和白细胞粘附询问。在我们正在进行的实验中， 与较小的粘附相关，而较大的粘附与溶血相关。初步 在纵向研究中，我们发现RBC粘附随着治疗的开始而下降，并且粘附水平 在稳定治疗的患者中稳定。根据我们的初步发现，我们假设，在SCD中：（1）改变 红细胞或白细胞粘附的变化将反映受试者的临床状态和治疗反应，以及（2） 粘附特性随年龄而变化，在血管闭塞性危象期间儿童和成人的粘附特性不同 （VOC）。 为了验证这些假设，我们提出了以下不同但相互关联的具体目标：目标1： 标准化大规模人群中多种细胞粘附特性的同时基线评价 无症状成人和儿童（在多个中心和纵向）;目的2：确定 血管闭塞危象期间存在的细胞粘附特性较基线的变化，以及 分析成人和儿童人群中的这些;目的3：检查细胞粘附的变化， 治疗干预前后的性质，包括输血、羟基脲和靶向抗- 粘连疗法我们的研究将提供一个更精确的表征异常粘附事件在一个 给予个体和更准确的整体治疗反应评估。中国愿 粘附试验在SCD中是可行的，并且具有临床意义，就像葡萄糖试验在糖尿病中一样。