Novel insights on immune thrombocytopenia purpura with platelet contraction cytometry

血小板收缩细胞术对免疫性血小板减少性紫癜的新见解

• 批准号: 10686169
• 负责人: Oluwamayokun Oshinowo
• 金额: $ 5.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-19 至 2026-08-18
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686169
• 关键词: Actins; Address; Adult; Adverse effects; Affect; Antibodies; Architecture; Biological; Biological Assay; Biological Markers; Biomedical Engineering; Biomedical Research; Biophysics; Blood; Blood Coagulation Disorders; Blood Platelets; Cells; Characteristics; Child; Clinical; Clinical Data; Contusions; Cytometry; Cytoskeleton; Data; Data Correlations; Data Set; Development; Diagnosis; Diagnostic tests; Disease; Endowment; Engineering; Enrollment; Exposure to; Fibrin; Flow Cytometry; Foundations; Goals; Grant; Hematological Disease; Hematology; Hemorrhage; Idiopathic Thrombocytopenic Purpura; Immature Platelet; Immune; Immune system; Immunofluorescence Immunologic; Immunoglobulin G; Impairment; Individual; Intracranial Hemorrhages; Intrinsic factor; Investigation; Lead; Learning; Life; Life Experience; Measurement; Measures; Medical; Medicine; Microfluidics; Monitor; Morphology; Myosin ATPase; Nature; PAC1 phosphatase; Patient Care; Patient risk; Patient-Focused Outcomes; Patients; Pediatric cohort; Phenotype; Physicians; Plasma; Platelet Activation; Platelet Count measurement; Platelet Function Tests; Purpura; RNA; Research; Resolution; Risk; Sampling; Scientist; Severities; Signal Pathway; Stains; Symptoms; System; Techniques; Technology; Testing; Thrombelastography; Thrombocytopenic Purpura; Time; Training; Treatment Side Effects; biophysical analysis; biophysical properties; career; clinical diagnostics; cohort; demographics; diagnostic biomarker; experience; high risk; improved; insight; medical attention; microdevice; novel; novel therapeutic intervention; pediatric patients; platelet function; pre-doctoral; prospective; receptor; side effect; skills; thiazole orange; tool; unnecessary treatment

PROJECT SUMMARY/ABSTRACT Defined by a low platelet count in the absence of any other cause, immune thrombocytopenic purpura (ITP) affects over 4,000 US children and 8,000 adults each year. While the majority of ITP cases resolve themselves, patients with ITP have an enhanced risk of bleeding, with 10% experiencing major bleeding, and 0.5% of experiencing life-threatening intracranial hemorrhage. Currently, there is no accurate biomarker or diagnostic test that assesses the bleeding risk in ITP and all therapies potentially cause significant side effects. This leaves clinicians with a significant dilemma in deciding whether or not to treat. Patients who are ultimately at high risk may not receive treatment until serious bleeding occurs, and low risk patients may be exposed to unnecessary treatment side effects. The research objective of this proposal is to investigate a novel hypothesis, namely, that the contractile force of individual platelets correlates with bleeding phenotype in ITP, independent of traditionally used biological markers or assays of hematological function. Using a technique developed by our lab, a high-throughput platelet contraction cytometer (PCC), to measure platelet contractile forces at the single cell level, our latest results of a study of pediatric patients with primary ITP suggests that platelet forces 1) vary significantly from healthy controls, 2) strongly correlate with bleeding and 3) change over time in the same patient. Aim 1 builds on this preliminary data and proposes a rigorous investigation into the relationship between contractile force, platelet characteristics, and clinical endpoints by studying a cohort of newly enrolled ITP patients at a single time point and prospectively for 12 months. We will specifically see if platelet contractile force correlates with bleeding score, immature platelet fraction, platelet activation, platelet morphology, patient demographics, and treatments. The PCC also offers a unique opportunity to gain new insights into the function of platelets from patients with ITP and mechanistic underpinnings of low force. Previous studies were hindered as traditional tools of platelet function such as aggregometry, platelet functional analyzers, or thromboelastography are confounded by the low platelet count in ITP. We will use the PCC to test our hypothesis that both intrinsic platelet changes and extrinsic plasma factors modify platelet contractile force. From an extrinsic perspective, our data has shown that the presence of anti-platelet IgG antibodies correlates with more severe bleeding and lower contractile forces. From an intrinsic perspective, we have found that patients with low mean platelet volume have lower platelet force and increased bleeding symptoms. As the mechanistic underpinnings are unclear, Aim 2 seeks to perform systematic, unbiased investigation into both the intrinsic and extrinsic factors that may modulate platelet function. This F31-diversity predoctoral training grant will allow me to push forward and satisfy my learning and career objectives, while simultaneously enhancing my training in diverse technical, computational and medical topics, that will only contribute to my development as a physician scientist devoted to Hematology in both medicine and research as I plan to pursue a career in academic medicine.

项目摘要/摘要 在没有任何其他原因的情况下，由低血小板计数定义 （ITP）每年影响4,000多名美国儿童和8,000名成年人。而大多数ITP案例解决 ITP患者本身的出血风险增加，有10％的患者出血，并且 0.5％的经历威胁生命的颅内出血。目前，没有准确的生物标志物或 评估ITP的出血风险和所有疗法的诊断测试可能会引起重大副作用。 这使临床医生在决定是否治疗时遇到了严重的困境。最终的患者 高风险可能直到发生严重出血，而低风险患者可能会受到治疗 不必要的治疗副作用。该提议的研究目的是研究一个新的假设， 也就是说，单个血小板的收缩力与ITP中的出血表型相关，独立 传统使用的生物学标记或血液学功能的测定法。使用我们开发的技术 实验室，一种高通量血小板收缩细胞仪（PCC），以测量单个的血小板收缩力 细胞水平，我们对原发性ITP的小儿患者研究的最新结果表明血小板力1） 2）显着从健康对照组中，与出血密切相关，3）随着时间的推移变化 病人。 AIM 1建立在此初步数据的基础上，并对 收缩力，血小板特征和临床终点，通过研究新招募的ITP队列 患者在一个时间点，前瞻性12个月。我们将明确查看血小板收缩力是否 与出血评分，未成熟的血小板分数，血小板激活，血小板形态相关，患者 人口统计和治疗。 PCC还提供了一个独特的机会来获得对功能的新见解 来自ITP患者的血小板和低力的机械基础。以前的研究受到阻碍 作为血小板功能的传统工具，例如聚集，血小板功能分析仪或 血栓射击被ITP中的低血小板计数混淆。我们将使用PCC检验我们的假设 内在血小板变化和外部等离子体因子都会改变血小板收缩力。来自外部 透视图，我们的数据表明，抗血小板IgG抗体的存在与更严重的 流血和下收缩力量。从固有的角度来看，我们发现平均较低的患者 血小板体积具有较低的血小板力和增加的出血症状。作为机械基础 尚不清楚，目标2试图对内在和外在因素进行系统的，无偏见的研究 这可能会调节血小板功能。这种F31多样性培训赠款将使我推动 并满足我的学习和职业目标，同时增强了我在各种技术方面的培训， 计算和医学主题，这只会有助于我作为一名医师科学家的发展 当我打算从事学术医学职业时，医学和研究中的血液学。

项目成果

An economical in-class sticker microfluidic activity develops student expertise in microscale physics and device manufacturing.

经济的课堂贴纸微流体活动可以培养学生在微观物理和设备制造方面的专业知识。

• DOI: 10.1039/d3lc00912b
• 发表时间: 2024
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Delgado,Priscilla;Luna,CAlessandra;Dissanayaka,Anjana;Oshinowo,Oluwamayokun;Waggoner,JesseJ;Schley,Sara;Fernandez,Todd;Myers,DavidR
• 通讯作者: Myers,DavidR

Universal pre-mixing dry-film stickers capable of retrofitting existing microfluidics.

通用预混合干膜贴纸能够改造现有的微流体。

• DOI: 10.1063/5.0122771
• 发表时间: 2023
• 期刊: Biomicrofluidics
• 影响因子: 3.2
• 作者: Delgado,P;Oshinowo,O;Fay,ME;Luna,CA;Dissanayaka,A;Dorbala,P;Ravindran,A;Shen,L;Myers,DR
• 通讯作者: Myers,DR