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.

项目概要/摘要 免疫性血小板减少性紫癜的定义是在没有任何其他原因的情况下血小板计数低 (ITP) 每年影响超过 4,000 名美国儿童和 8,000 名成人。虽然大多数 ITP 案件都能得到解决 ITP 患者本身出血风险较高，10% 的患者经历大出血，并且 0.5% 的人经历危及生命的颅内出血。目前尚无准确的生物标志物或 评估 ITP 出血风险的诊断测试和所有疗法都可能导致显着的副作用。 这让临床医生在决定是否治疗时陷入了严重的困境。最终的患者 高风险患者可能直到发生严重出血才接受治疗，低风险患者可能会接触到 不必要的治疗副作用。该提案的研究目标是研究一个新的假设， 即，单个血小板的收缩力与 ITP 的出血表型相关，独立的 传统使用的生物标记或血液学功能测定。使用我们开发的技术 实验室，高通量血小板收缩细胞仪（PCC），用于测量单次血小板收缩力 细胞水平上，我们对原发性 ITP 儿科患者的最新研究结果表明，血小板力量 1) 有所不同 与健康对照显着不同，2）与出血密切相关，3）同一时间随时间变化 病人。目标 1 建立在这些初步数据的基础上，并提出对两者之间的关系进行严格的调查 通过研究一组新入组的 ITP 来了解收缩力、血小板特征和临床终点 单个时间点和前瞻性 12 个月的患者。我们将具体观察血小板收缩力是否 与出血评分、未成熟血小板分数、血小板活化、血小板形态、患者相关 人口统计和治疗。 PCC 还提供了一个独特的机会来获得对该功能的新见解 ITP 患者的血小板和低力的机械基础。之前的研究受到阻碍 作为血小板功能的传统工具，例如聚集测定法、血小板功能分析仪或 血栓弹力图因 ITP 患者血小板计数低而受到干扰。我们将使用 PCC 来检验我们的假设 内在血小板变化和外在血浆因素都会改变血小板收缩力。来自外在的 从角度来看，我们的数据表明，抗血小板 IgG 抗体的存在与更严重的症状相关。 出血和收缩力降低。从内在的角度来看，我们发现平均数较低的患者 血小板体积有血小板力降低和出血症状增加。作为机械基础 尚不清楚，目标 2 寻求对内在和外在因素进行系统、公正的调查 可能调节血小板功能。 F31-多样性博士前培训补助金将使我能够继续前进 满足我的学习和职业目标，同时加强我在各种技术、 计算和医学主题，这只会有助于我作为一名致力于医学科学家的发展 因为我计划从事学术医学事业，所以我转向了血液学医学和研究。

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