Thrombolysis Profiles in tPA Response

tPA 反应中的溶栓曲线

• 批准号: 8956002
• 负责人: Eng H. Lo
• 金额: $ 38.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8956002
• 关键词: Acute; Affect; Age; Albumins; Alteplase; Binding; Binding Proteins; Bioinformatics; Biological; Blood; Blood Circulation; Blood Coagulation Factor; Characteristics; Clinical; Coagulation Process; Comorbidity; Cytolysis; Data; Diabetes Mellitus; Disabled Persons; Dose; Enrollment; Equilibrium; Failure; Figs - dietary; Gender; Half-Life; Hospitals; Hour; Human; Individual; Institutional Review Boards; Intravenous; Ischemic Stroke; Laboratories; Mass Spectrum Analysis; Measurable; Measures; Methods; Monitor; Multicenter Studies; National Institute of Neurological Disorders and Stroke; Outcome; Outcome Measure; Pathway interactions; Patients; Pilot Projects; Plasma; Play; Proteins; Proteomics; Publishing; Research Design; Role; Sensitivity and Specificity; Severities; Signal Transduction; Specificity; Stroke; Techniques; Time; VWF gene; Work; base; clinical effect; cohort; diabetic; diabetic patient; effective therapy; glycosylated serum albumin; improved; innovation; medical schools; meetings; non-diabetic; novel; novel marker; public health relevance; response; thrombolysis; transcriptomics; Acute; Affect; Age; Albumins; Alteplase; Binding; Binding Proteins; Bioinformatics; Biological; Blood; Blood Circulation; Blood Coagulation Factor; Characteristics; Clinical; Coagulation Process; Comorbidity; Cytolysis; Data; Diabetes Mellitus; Disabled Persons; Dose; Enrollment; Equilibrium; Failure; Figs - dietary; Gender; Half-Life; Hospitals; Hour; Human; Individual; Institutional Review Boards; Intravenous; Ischemic Stroke; Laboratories; Mass Spectrum Analysis; Measurable; Measures; Methods; Monitor; Multicenter Studies; National Institute of Neurological Disorders and Stroke; Outcome; Outcome Measure; Pathway interactions; Patients; Pilot Projects; Plasma; Play; Proteins; Proteomics; Publishing; Research Design; Role; Sensitivity and Specificity; Severities; Signal Transduction; Specificity; Stroke; Techniques; Time; VWF gene; Work; base; clinical effect; cohort; diabetic; diabetic patient; effective therapy; glycosylated serum albumin; improved; innovation; medical schools; meetings; non-diabetic; novel; novel marker; public health relevance; response; thrombolysis; transcriptomics

 DESCRIPTION (provided by applicant): Intravenous tissue plasminogen activator (tPA) is an effective treatment for acute ischemic stroke, but nearly two decades after FDA approval, its utilization remains low, and up to 80% of patients who receive tPA show no beneficial response. Currently, neither the mechanisms underlying tPA's effects in human blood nor the reasons for most patients' failure to respond are well understood. In order to develop clinical methods of monitoring tPA's activity in blood in real time, to guide treatment for individual patients, we aim to better understand tPA's clinical effects, especially with respect to its pleiotropic signaling within the blood. We hypothesize that tPA efficacy has a measurable and quantifiable signature in the circulation, and that perturbation of a delicate balance in coagulation and thrombolysis pathways is related to poor efficacy. Comparing tPA responders vs. non-responders, we employ a combined approach including conventional as well as innovative mass spectrometry (MS) techniques. As points of entry, we focus on two aspects that our preliminary data suggest are pivotal: the ADAMTS13/vWF pathway which plays a role in clot formation and lysis and is affected by tPA, and glycated albumin, which may sequester tPA leading to poorer outcomes for diabetic patients. Aim 1: Characterize tPA response by exploring the ADAMTS13/vWF axis/pathway, measuring levels of ADAMTS13 and vWF, and assessing ADAMTS13 activity by means of ADAMTS13-specific vWF substrate fragments, in responders vs. non-responders. We hypothesize that tPA responders will have elevated ADAMTS13 levels and activity, and decreased vWF. Aim 2: Investigate non-response in diabetic stroke patients by exploring the role of glycated albumin, high levels of which are characteristic of diabetes. We hypothesize that glycated albumin is higher in nonresponders, and that glycated albumin sequesters tPA, thereby diminishing tPA's efficacy in diabetic patients. We will use innovative proteomic techniques to examine the molecules "stuck" to albumin in individual patients' blood, and we hypothesize that glycated albumin sequesters more tPA than non-glycated albumin. With three collaborating US centers (MGH, BWH, UMass Medical School), and a fourth separate confirmation cohort (Vall d'Hebron Hospital, Barcelona) - we are able to enroll patients at a pace sufficient for our most conservative power calculation based on preliminary data. Our encouraging pilot data, IRB-approved published SOP and detailed analysis plan for longitudinal measures of outcome, adjusting for multiple co-morbidities, demonstrate the feasibility of recruitment and analysis, and directly support our hypotheses and approach.

 描述（由应用提供）：静脉组织纤溶酶原激活剂（TPA）是一种有效的急性缺血性中风的治疗方法，但是在FDA批准后将近二十年，其利用率仍然较低，多达80％的接受TPA的患者没有表现出任何有益反应。目前，对TPA在人血液中的影响的基础机制和大多数患者无法做出反应的原因均未得到充分了解。为了开发实时监测TPA血液活性的临床方法，以指导个别患者的治疗 为了更好地了解TPA的临床效果，尤其是关于其血液中的多效信号传导。我们假设TPA效率在循环中具有可测量且可量化的签名，并且在凝血和溶栓途径中微妙平衡的扰动与效率差有关。比较TPA响应者与非反应者，我们采用了一种联合方法，包括常规和创新质谱（MS）技术。作为入口点，我们关注的两个方面是我们的初步数据表明的两个方面是关键：ADAMTS13/VWF途径，该途径在凝块形成和溶解中发挥作用，受TPA的影响，以及TPA的影响，以及糖化白蛋白，可能会导致糖尿病患者造成较差的TPA。 AIM 1：通过探索ADAMTS13/VWF轴/途径，测量ADAMTS13和VWF的水平以及评估ADAMTS13通过ADAMTS13特异性vwf底物的活性来表征TPA响应。我们假设TPA响应者将具有升高的ADAMTS13水平和活动，并扩大了VWF。 AIM 2：通过探索糖化白蛋白的作用，研究糖尿病性中风患者的无反应，其高水平是糖尿病的特征。我们假设在非反应者中糖化白蛋白较高，并且糖化白蛋白隔离剂TPA，从而降低了TPA在糖尿病患者中的有效性。我们将使用创新的蛋白质组学技术来检查单个患者血液中白蛋白的分子“卡住”，我们假设糖化白蛋白隔离比非糖化白蛋白更为tpa。拥有三个合作的美国中心（MGH，BWH，UMASS医学院），并设有第四个单独的确认队列（巴塞罗那Vall d'Hebron医院） - 我们能够在基于初步数据的基于我们最保守的电源计算的空间中让患者招募患者。我们令人鼓舞的试点数据，IRB批准的已发表的SOP和详细的分析计划，以进行纵向测量结果，调整多种合并症，证明了招聘和分析的可行性，以及 直接支持我们的假设和方法。