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: 10444288
• 负责人: DAVID SIGMUND LIEBESKIND
• 金额: $ 71.27万
• 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/10444288
• 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; 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; Population Heterogeneity; 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; Time; Transient Ischemic Attack; Universities; Vermont; Work; adjudication; base; 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; 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.

项目摘要/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]和壁剪应力（WSS）的血小板表达来自患者特异性CT 血管造影（CTA）计算流体动力学（CFD）[SA-2]来解释次要的复发性缺血 由于ICAD而导致的中风或TIA。开发了一个精确模型[SA-3]，以量化复发性缺血性损伤的风险， 在潜水员中，占FcγRIIA，WSS，抗血域疗法和血小板反应性的影响 中风和ICAD的TIA患者。我们的中心假设是高FcγRIIA和高剪切力姿势 中风复发的个人和协同风险，为精确医学提供了合理的基础 ICAD预防中风。我们的初步数据表明，较高的血小板FcγRIIA表达识别 复发性心血管事件的风险更大，包括中风和CTA CFD上的高WSS 预测1年时ICAD引起的中风会复发。我们的三个独立特定目标利用了已建立的 具有种族族裔潜水员的6个地理上不同的网站的研究基础设施和ICAD网络 人口和产品合作的长期历史，招募250名参与者 症状发作72小时内，脑缺血。多中心，观察性研究将注册中风 或TIA患者由于经常获得的CTA诊断为50-99％的ICAD，并获得脑MRI和血液 在72小时内进行FCγRIIA和血小板测定的采样，并在发病后1年再次采样。临床结果将 在90天和1年时确定，并共同注册串行MRI，以量化间隔的沉默和 有症状的缺血性损伤。佛蒙特大学的血小板生物学核心将量化血小板FcγRIIA 表达。 UCLA的神经血管成像研究核心将进行中心成像分析， 包括WSS的CTA CFD量化，串行MRI共同注册和资格的成像调整 和间隔端点。统计核心将协调来自6个注册站点的数据管理和 核心设施，进行预测统计，关键生物学变量的分层以及新的应用 聚类分析策略在1年时最大程度地告知ICAD中风风险的精确模型。这个及时 ICAD中剪切应力诱导的血小板激活的协同工作的高潮利用了我们的稳健 关于FcγRIIA，WSS的CTA CFD和中风的精确医学分析的初步数据 多中心，观察性研究的成功记录是最常见的重复中风原因。 测量由异源伪像引起的FcγRIIA和剪切应力的个体差异 告知逻辑上的精确医学策略以避免中风。这种新颖的使用诊断数据的新颖策略 通过ICAD引起的中风或TIA后不久获得对临床翻译的明显影响 药物可以实现个性化的中风治疗，重点是血小板病理生理机制 解决临床事件以及由于斑块远端的复发性缺血而导致的沉默，阴险的脑损伤。