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.

项目总结/摘要 本提案的总体目标是确定个人的潜在关键和互动作用， 根据患者特异性CT计算的FcγRIIa [SA-1]血小板表达和壁剪切应力（WSS） 血管造影（CTA）计算流体动力学（CFD）[SA-2]，以解释轻微缺血后复发性缺血 中风或短暂性脑缺血发作开发了一种精确模型[SA-3]，以量化复发性缺血性损伤的风险， 考虑到FcγRIIa、WSS、抗血小板治疗和血小板反应性， 脑卒中和TIA合并ICAD患者。我们的中心假设是高FcγRIIa加上高剪切力使得 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。我们的初步数据显示，血小板FcγRIIa表达越高， 患者复发心血管事件（包括卒中）的风险较高，CTA CFD显示WSS较高 预测1年时ICAD导致的复发性卒中。我们的三个独立的具体目标利用一个既定的 研究基础设施和ICAD网络，由6个地理位置不同的注册地点组成， 人口和长期的富有成效的合作历史，招募250名急性 症状发作后72小时内发生脑缺血。这项多中心、观察性研究将招募卒中患者 或TIA患者，由于50-99%的ICAD在常规采集的CTA上诊断，并获得脑MRI和血液 在发病后72小时内和1年后再次采样进行FcγRIIa和血小板测定。临床结果将 在90天和1年时确定，同时配准系列MRI以量化无症状间期， 症状性缺血性损伤佛蒙特大学的血小板生物学核心将量化血小板FcγRIIa 表情加州大学洛杉矶分校的神经血管成像研究中心将进行中心成像分析， 包括WSS的CTA CFD量化、系列MRI配准和合格性的成像裁定 和区间端点。统计核心将协调6个入组研究中心的数据管理， 核心设施，进行预测统计，关键生物变量的分层和新的应用， 聚类分析策略，以最大限度地告知1年时ICAD卒中风险的精确模型。这一及时 在ICAD中剪切应力诱导的血小板活化的协同工作的高潮利用了我们强大的 关于FcγRIIa、WSS的CTA CFD和中风中的精确医学分析的初步数据，分层于 对复发性卒中最常见原因的多中心观察性研究的成功记录。 异质性动脉狭窄诱导的FcγRIIa和切应力的个体差异测量 告知一个合理的精确医疗策略来避免中风。这种轻松使用诊断数据的新策略 在中风或短暂性脑缺血发作后不久，由于ICAD而获得，通过精确的临床翻译， 使个体化中风治疗成为可能的药物，专注于血小板病理生理学机制， 解决了临床事件和由于斑块远端的复发性缺血引起的无症状、隐匿性脑损伤。