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 镰状血红蛋白突变遭受了全世界数百万的人的影响 发病率和死亡率。镰状细胞疾病（SCD）的病理生理学是异常的结果 脱氧镰状血红蛋白聚合及其对红细胞（RBC）的有害影响 膜，形状，密度，变形性和粘附。镰状红细胞的最初强大观察 此后对内皮细胞的异常粘附进行了加深并扩展以描述复合物 异常白细胞（WBC）粘附的病理生理学也起着重要作用。这些 研究导致利用靶向抗粘附疗法的临床试验开发。尽管有很大的见解 关于已经制作的SCD中异常细胞粘附，有关这些的知识仍然存在差距 复杂的粘合剂相互作用。没有既定的异常粘合剂事件的“地图集” 在大量的SCD患者中，以纵向和标准化的方式在A 临床情况范围以及没有治疗的情况。都不是粘合剂事件的地形 一个个体患者，也不适合整个SCD人群。更好地了解自然和 异常粘合剂事件的范围对于建立与临床结果的关联的目标至关重要 并成功识别临床试验中的治疗靶标。 我们已经开发了一种新型的微流体测定法，可以快速，预处理和标准化 全血中对RBC和WBC粘附的询问。在我们正在进行的实验中，高水平的HBF是 与较少的粘附相关，而更大的粘附与溶血有关。在初步 纵向研究，我们发现RBC粘附在治疗的开始下降，并且粘附水平 在稳定治疗的患者中稳定。鉴于我们的初步发现，我们假设在SCD中：（1）改变 在RBC或WBC粘附中，将反映受试者的临床状态和治疗反应，（2） 粘合剂的轮廓将随着年龄的增长而变化，在血管熟悉危机期间儿童和成人之间会有所不同 （VOC）。 为了检验这些假设，我们提出以下不同但相互关联的特定目的：目标1： 标准化大量人群中多个细胞粘合特性的基线评估 无症状的成年人和儿童（在一个以上的中心和纵向上）；目标2：确定 在血管结合危机期间存在的细胞粘合特性中的基线变化，并 在成人和小儿种群中分析这些；目标3：检查细胞粘合剂的变化 治疗干预之前和之后的特性，包括输血，羟基脲和靶向抗 粘附疗法。我们的研究将提供更精确的表征在某人中的异常粘合剂事件 给定个人和对治疗反应的整体评估。我们想 在SCD中，作为可行的粘附测试是可行的，并且在临床上是有意义的，因为糖尿病是葡萄糖测试。