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

项目摘要/摘要 这项建议的总体目标是确定个人潜在的关键和互动角色 从患者特异性CT计算FcγRIIA[SA-1]和壁切应力的血小板表达 血管造影术(CTA)计算流体动力学(CFD)[SA-2]解释微小缺血后复发 ICAD导致的中风或短暂性脑缺血发作。开发了一个精确的模型[SA-3]来量化复发的缺血性损伤的风险， 在不同的人群中，FcγRIIA，WSS，抗血小板治疗和血小板反应性 卒中和短暂性脑缺血发作患者合并ICAD。我们的中心假设是高FCγRIIA加上高剪切力姿势 中风复发的个体和协同风险，为精准医学提供了合理的依据 ICAD中的中风预防。我们的初步数据显示，较大的血小板FcγRIIA表达可识别 中风和CTA CFD上WSS高的患者发生复发心血管事件的风险更高 预测1年后因ICAD而复发的中风。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个地理位置不同的不同种族和民族的招生地点组成 人口和长期的生产性协作历史，招募了250名具有急性 症状出现后72小时内出现脑缺血。这项多中心的观察性研究将纳入中风 或TIA患者，因为50%-99%的ICAD是在常规获得的CTA上诊断的，并获得了脑MRI和血液 在发病72小时内和发病1年后再次抽血进行FC、γ、放射免疫分析和血小板检测。临床结果将 在90天和1年后确定，并进行序列MRI联合注册，以量化静默和 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央成像分析， 包括WSS的CTA CFD量化、序列MRI联合配准和符合条件的成像判定 和区间端点。统计核心将协调来自6个登记地点的数据管理和 核心设施，进行预测统计，关键生物变量的分层和新的应用 分类分析策略，最大限度地提供ICAD卒中风险1年的精确模型。这来得正是时候 在ICAD中，剪切力诱导的血小板激活的协同工作达到顶峰，利用我们的强大 关于中风的FCγRIIA、CTA CFD和中风的精确医学分析的初步数据，基于 对中风复发最常见原因的多中心观察性研究的成功记录。 异质性动脉狭窄引起的Fc、γ、RIA和切应力的个体差异测量 提供合理的精准医疗策略，以避免中风。这一轻松使用诊断数据的新策略 ICAD导致的卒中或短暂性脑缺血发作后不久获得的信息对通过精确度进行临床翻译具有明显的意义 能够个体化治疗中风的医学，重点是血小板的病理生理机制，而 处理临床事件和由于斑块远端反复缺血而造成的静默、潜伏的脑损伤。

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.