Platelet Expression of FcgammaRIIa and Arterial Hemodynamics to Predict Recurrent Stroke in Intracranial Atherosclerosis

FcgammaRIIa 的血小板表达和动脉血流动力学预测颅内动脉粥样硬化复发性中风

• 批准号: 10588179
• 负责人: DAVID SIGMUND LIEBESKIND
• 金额: $ 63.22万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588179
• 关键词: 3-Dimensional; Accounting; Acute; Address; Age; Agonist; Angiography; Architecture; Arteries; Biological; Biological Assay; Biology; Blood Platelets; Blood flow; Blood specimen; Brain; Brain Injuries; Cardiovascular system; Cerebral Ischemia; Clinical; Collaborations; Core Facility; Coronary Arteriosclerosis; Coronary Circulation; Data; Diagnostic; Disparity; Distal; Eligibility Determination; Enrollment; Ethnic Origin; Event; Exposure to; Functional disorder; Geography; Goals; Heterogeneity; Hour; Hypertension; Image; Incidence; Individual; Individual Differences; Injury; Intracranial Atherosclerotic Disease; Ischemia; Ischemic Stroke; Liquid substance; Magnetic Resonance Imaging; Measurement; Minor; Modeling; Multicenter Studies; Observational Study; Outcome; Participant; Pathology; Patients; Pattern; Pharmaceutical Preparations; Platelet Activation; Platelet Aggregation Induction; Platelet aggregation; Population Heterogeneity; Productivity; Public Health; Race; Recording of previous events; Recurrence; Research; Research Infrastructure; Risk; Risk Factors; Role; Serial Magnetic Resonance Imaging; Site; Statistical Models; Stenosis; Stimulus; Stratification; Stroke; Stroke prevention; Symptoms; Thrombosis; Transient Ischemic Attack; Universities; Vermont; Work; adjudication; brain magnetic resonance imaging; cerebrovascular; clinical translation; comorbidity; data management; disability; disease diagnosis; ethnic diversity; hemodynamics; indexing; individualized medicine; ischemic injury; mechanical force; neurovascular; novel; novel strategies; post stroke; precision medicine; prevent; racial diversity; recruit; response; sex; shear stress; statistics; stroke risk; stroke therapy; synergism

PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to determine the potentially pivotal and interactive roles of individual platelet expression of FcγRIIa [SA-1] and wall shear stress (WSS) calculated from patient-specific CT angiography (CTA) computational fluid dynamics (CFD) [SA-2] to explain recurrent ischemia after minor stroke or TIA due to ICAD. A precision model is developed [SA-3] to quantify risk of recurrent ischemic injury, accounting for FcγRIIa, WSS, anti-platelet therapies and platelet reactivity, across a diverse population of stroke and TIA patients with ICAD. Our central hypothesis is that high FcγRIIa plus high shear force pose individual and synergistic risk of stroke recurrence, providing a rational basis for the precision medicine of stroke prevention in ICAD. Our preliminary data reveal that greater platelet FcγRIIa expression identifies patients at greater risk of recurrent cardiovascular events including stroke and that high WSS on CTA CFD predicts recurrent stroke due to ICAD at 1 year. Our three independent specific aims leverage an established research infrastructure and ICAD network of 6 geographically distinct enrolling sites with race-ethnic diverse populations and a longstanding history of productive collaboration to recruit 250 participants with acute cerebral ischemia within 72 hours from symptom onset. The multicenter, observational study will enroll stroke or TIA patients due to 50-99% ICAD diagnosed on routinely acquired CTA and obtain brain MRI and blood sampling for FcγRIIa and platelet assays within 72 hours and again at 1 year after onset. Clinical outcomes will be ascertained at 90 days and at 1 year, with co-registration of serial MRI to quantify interval silent and symptomatic ischemic injury. The Platelet Biology Core at University of Vermont will quantify platelet FcγRIIa expression. The Neurovascular Imaging Research Core at UCLA will conduct central imaging analyses, including CTA CFD quantification of WSS, serial MRI co-registration and imaging adjudication of eligibility and interval endpoints. The Statistical Core will coordinate data management from 6 enrolling sites and the core facilities, conducting predictive statistics, stratification of key biological variables and novel application of clustering analytic strategies to maximally inform a precision model of ICAD stroke risk at 1 year. This timely culmination of synergistic work on shear stress-induced platelet activation in ICAD leverages our robust preliminary data on FcγRIIa, CTA CFD of WSS and precision medicine analytics in stroke, layered on a successful track record of multicenter, observational studies of the most common cause of recurrent stroke. Measurement of individual differences in FcγRIIa and shear stress induced by heterogenous arterial stenoses inform a logical precision medicine strategy to avert stroke. This novel strategy of using diagnostic data easily acquired shortly after stroke or TIA due to ICAD has clear implications for clinical translation via precision medicine enabling individualized stroke treatment, focused on mechanisms of platelet pathophysiology while addressing clinical events and silent, insidious brain damage due to recurrent ischemia distal to the plaque.

项目概要/摘要 该提案的总体目标是确定个人的潜在关键和互动作用 FcγRIIa [SA-1] 的血小板表达和根据患者特异性 CT 计算的壁剪切应力 (WSS) 血管造影 (CTA) 计算流体动力学 (CFD) [SA-2] 解释轻微后复发性缺血 ICAD 引起的中风或 TIA。开发了精确模型 [SA-3] 来量化复发性缺血性损伤的风险， 解释不同人群中的 FcγRIIa、WSS、抗血小板治疗和血小板反应性 患有 ICAD 的中风和 TIA 患者。我们的中心假设是高 FcγRIIa 加上高剪切力构成 脑卒中复发的个体和协同风险，为精准医疗提供合理依据 ICAD 中的中风预防。我们的初步数据表明，较高的血小板 FcγRIIa 表达可识别 复发性心血管事件（包括中风）风险较高的患者以及 CTA CFD 上的高 WSS 预测 1 年后因 ICAD 导致的复发性中风。我们的三个独立的具体目标利用了既定的 研究基础设施和 ICAD 网络，由 6 个地理位置不同且种族多样化的招生地点组成 人口和长期富有成效的合作历史，招募 250 名参与者 症状出现后 72 小时内发生脑缺血。这项多中心观察性研究将招募中风患者 或由于 50-99% ICAD 导致的 TIA 患者通过常规 CTA 诊断并获得脑部 MRI 和血液 发病后 72 小时内和 1 年后再次取样进行 FcγRIIa 和血小板测定。临床结果将 在第 90 天和第 1 年确定，并联合配准系列 MRI 以量化沉默和沉默间隔 有症状的缺血性损伤。佛蒙特大学血小板生物学核心将量化血小板 FcγRIIa 表达。加州大学洛杉矶分校的神经血管成像研究核心将进行中央成像分析， 包括 WSS 的 CTA CFD 量化、系列 MRI 联合注册和资格成像判定 和区间端点。统计核心将协调 6 个注册站点和 核心设施，进行预测统计，关键生物变量的分层和新应用 聚类分析策略，最大限度地为 1 年 ICAD 中风风险的精确模型提供信息。这个及时 ICAD 中剪切应力诱导的血小板激活的协同工作的顶峰利用了我们强大的 FcγRIIa、WSS 的 CTA CFD 和中风精准医学分析的初步数据，分层 针对复发性中风最常见原因的多中心观察性研究的成功记录。 FcγRIIa 个体差异和异质动脉狭窄引起的剪切应力的测量 提供合理的精准医疗策略来避免中风。这种轻松使用诊断数据的新颖策略 因 ICAD 导致的中风或 TIA 后不久获得的数据通过精确度对临床转化具有明显的影响 医学能够实现个体化中风治疗，重点关注血小板病理生理学机制，同时 解决由于斑块远端反复缺血引起的临床事件和无声、隐匿的脑损伤。