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: 9975877
• 负责人: Umut A. Gurkan
• 金额: $ 39.32万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975877
• 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; Deoxygenated Sickle Hemoglobin; Development; Diabetes Mellitus; Drops; E-Selectin; Endothelial Cells; Erythrocytes; Evaluation; Event; Fetal Hemoglobin; Fibronectins; Financial Hardship; Functional disorder; Glucose; Goals; Hemoglobin SC Disease; Hemolysis; Hypoxemia; Individual; Knowledge; Laminin; Leukocytes; Longitudinal Studies; Measurement; Measures; Microfluidics; Monitor; Morbidity - disease rate; Mutation; Nature; 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 database; clinical investigation; density; experience; experimental study; hydroxyurea; improved; individual patient; insight; mortality; novel; painful neuropathy; polymerization; response; sickling; therapeutic target; treatment response; vaso-occlusive crisis

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.

项目总结 镰状血红蛋白突变困扰着全球数百万人，并与相当大的 发病率和死亡率。镰刀细胞病(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的毒害作用 膜、形状、密度、变形性和附着力。最初强有力的观察表明，镰刀状的红细胞 显示对内皮细胞的异常黏附后来被加深和扩大，以描述一种复合体 其中白细胞(WBC)的异常黏附在病理生理学中也起着重要作用。这些 研究导致了使用靶向抗粘连疗法的临床试验开发。尽管有非凡的见解 关于SCD中的异常细胞黏附，人们对此仍然知之甚少 复杂的粘合剂相互作用。没有检查过的异常粘连事件的已建立的“图集” 以纵向和标准化的方式在大量不同类型的SCD患者中进行研究 临床情况的范围以及接受和不接受治疗。既不是粘性事件的地形 目前尚不清楚单个患者，也不知道整个SCD人群。更好地了解大自然和 异常粘连事件的范围对于建立与临床结果相关的目标至关重要 并在临床试验中成功地确定了治疗靶点。 我们已经开发了一种新的微流控分析方法，它允许快速、免前处理和标准化 全血中红细胞和白细胞粘附性的检测。在我们正在进行的实验中，高水平的HBF是 粘附性较弱，而粘附性较强则与溶血有关。在预赛中 纵向研究发现，随着治疗的开始，红细胞粘附性下降，并且粘附性水平 在稳定治疗的患者中是稳定的。根据我们的初步发现，我们假设，在SCD中：(1)变化 在RBC或WBC中的粘附会反映受试者的临床状态和治疗反应，以及(2) 粘附性特征会随着年龄的增长而改变，在血管闭塞危象期间，儿童和成人的粘附性特征会有所不同。 (VOCs)。 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： 使大规模人群中多种细胞黏附特性的同时基线评估标准化 无症状成人和儿童(在一个以上的中心和纵向)；目标2：确定 血管闭塞危象期间出现的细胞黏附特性与基线的变化，以及 在成人和儿童人群中分析这些；目标3：检查细胞黏附的变化 治疗干预前后的性质，包括输血、羟基脲和靶向抗心磷脂 粘连疗法。我们的研究将提供对异常粘连事件的更准确的描述 考虑到个体和更准确的总体治疗反应评估。我们想做一件 粘附性试验在SCD中是可行的，而且在临床上有意义，就像血糖检测在糖尿病中一样。

项目成果

Biophysical and rheological biomarkers of red blood cell physiology and pathophysiology.

• DOI: 10.1097/moh.0000000000000639
• 发表时间: 2021-05-01
• 期刊: Current opinion in hematology
• 影响因子: 3.2
• 作者: Gurkan UA

Size and density measurements of single sickle red blood cells using microfluidic magnetic levitation.

• DOI: 10.1039/d1lc00686j
• 发表时间: 2022-02-15
• 期刊: Lab on a chip
• 影响因子: 6.1

Sickle cell disease biochip: a functional red blood cell adhesion assay for monitoring sickle cell disease.

• DOI: 10.1016/j.trsl.2016.03.008
• 发表时间: 2016-07
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Alapan Y;Kim C;Adhikari A;Gray KE;Gurkan-Cavusoglu E;Little JA;Gurkan UA
• 通讯作者: Gurkan UA

Priapism, hemoglobin desaturation, and red blood cell adhesion in men with sickle cell anemia.

镰状细胞性贫血男性的阴茎异常勃起、血红蛋白去饱和和红细胞粘附。

• DOI: 10.1016/j.bcmd.2019.102350
• 发表时间: 2019
• 期刊: Blood cells, molecules & diseases
• 作者: Yuan,Charlotte;Quinn,Erina;Kucukal,Erdem;Kapoor,Sargam;Gurkan,UmutA;Little,JaneA
• 通讯作者: Little,JaneA