Treatment Targets for Inflamed Intracranial Atherosclerosis on Vessel Wall MRI

血管壁 MRI 治疗炎症性颅内动脉粥样硬化的目标

• 批准号: 10396018
• 负责人: Adam H. de Havenon
• 金额: $ 19.42万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396018
• 关键词: Advisory Committees; Angiography; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Autopsy; Biological Markers; Biology; Biometry; Blocking Antibodies; Blood; Blood Circulation; Blood Vessels; Caliber; Carotid Arteries; Carotid Atherosclerotic Disease; Cerebrovascular system; Clinical Research; Clinical Trials; Clinical Trials Design; Clinical assessments; Complement; Data; Development; Discipline; Disease; Enrollment; Epidemiology; Evaluation; Evolution; Future; Gadolinium; Goals; Hour; Imaging Techniques; Inflammation; Intracranial Atherosclerotic Disease; Iron; Ischemic Stroke; Label; Lead; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Meta-Analysis; Methodology; Methods; Monoclonal Antibodies; Neurologist; Neurology; Operative Surgical Procedures; Parents; Patients; Persons; Pharmaceutical Preparations; Physiology; Pilot Projects; Play; Prevention trial; Recurrence; Refractory Disease; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Scientist; Signal Transduction; Stenosis; Stents; Stroke; Stroke prevention; Techniques; Testing; Therapeutic Uses; Time; Validation; Visual; Work; authority; base; brain magnetic resonance imaging; career; career development; cytokine; ferumoxytol; fight against; follow-up; high resolution imaging; high risk; histological studies; imaging biomarker; improved; innovation; insight; intracranial artery; macrophage; multimodality; nanoparticle; neuroimaging; next generation; novel; novel strategies; patient oriented; prevent; primary outcome; protocol development; radiological imaging; skills; stroke risk; uptake

PROJECT SUMMARY/ABSTRACT This is a K23 award application for Dr. Adam de Havenon, a neurologist and young investigator pursuing patient-oriented clinical research on ischemic stroke caused by intracranial atherosclerosis. A K23 award will provide him with the means to acquire critical skills in three key career development areas: 1) biostatistics and clinical trial design, 2), the biology of atherosclerosis and 3) translational MRI research. By acquiring these skills, Dr. de Havenon will fulfill his career goal of becoming an independent investigator who can bridge the disciplines of neuroimaging research and clinical trials in vascular neurology. To pursue this goal, Dr. de Havenon has assembled the mentoring team of Drs. Dennis Parker (primary mentor), an MRI physicist with expertise in neuroimaging evaluation of the cerebrovasculature, and Jennifer Majersik (co-mentor), a neurologist with expertise in stroke epidemiology and clinical trial design. Complementing them is a four person Advisory Committee with authorities in biostatistics, clinical trials, intracranial atherosclerosis, and MRI. Intracranial atherosclerosis is the most common cause of stroke in the world and has the highest rate of stroke recurrence. Based on recent evidence and his own preliminary data, Dr. de Havenon’s central hypothesis is that ischemic stroke in intracranial atherosclerosis is due to macrophage-mediated vulnerability. We will test this hypothesis with the powerful new vessel wall MRI technique combined with an MRI contrast that labels macrophages in intracranial atherosclerosis, which will allow the identification of innovative biomarkers of intracranial atherosclerosis stroke risk and potential treatment targets for future studies. By pursuing the following specific aims, the applicant will test his hypothesis and gather data for a clinical trial to reduce recurrent stroke risk in intracranial atherosclerosis (to be proposed in an R01 application during the K23 award period). Specific Aim 1 will test the hypothesis that ferumoxytol, the MRI contrast that labels macrophages, will be seen in arteries with intracranial atherosclerosis that recently caused stroke. Specific Aim 2 will test the hypothesis that arteries with intracranial atherosclerosis and ferumoxytol-labeled macrophages will have progression of the narrowing of the artery caused by intracranial atherosclerosis over a one-year period. Specific Aim 3 will test the hypothesis that arteries with intracranial atherosclerosis and ferumoxytol-labeled macrophages will have more strokes over a one-year period. The proposed research is significant because intracranial atherosclerosis is understudied and requires new approaches to reduce its risk. The proposed research is innovative because it combines an advanced imaging technique (vessel wall MRI) and a novel use of the macrophage-specific MRI contrast ferumoxytol, to provide multimodal insight into the mechanism of stroke from intracranial atherosclerosis that could be treated therapeutically using medications that target macrophages.

项目总结/摘要 这是一个K23奖的应用程序博士亚当德Havenon，神经学家和年轻的研究人员追求 以患者为中心的颅内动脉粥样硬化致缺血性脑卒中的临床研究。K23奖项将 为他提供在三个关键职业发展领域获得关键技能的方法：1）生物统计学， 临床试验设计，2）动脉粥样硬化的生物学和3）转化MRI研究。通过获取这些 技能，de Havenon博士将实现他的职业目标，成为一名独立的调查员， 神经影像学研究和血管神经学临床试验的学科。为了实现这一目标，德博士 Havenon已经组建了Dennis帕克博士（主要导师）的指导团队，他是一位MRI物理学家， 在神经影像学评估的专业知识，血管和詹妮弗Majersik（共同导师）， 具有卒中流行病学和临床试验设计专业知识的神经科医生。补充他们的是一个四人 生物统计学、临床试验、颅内动脉粥样硬化和MRI领域的权威咨询委员会。 颅内动脉粥样硬化是世界上最常见的中风原因， 中风复发根据最近的证据和他自己的初步数据，德·哈文农博士的中心 假设颅内动脉粥样硬化缺血性卒中是由于巨噬细胞介导的脆弱性。 我们将测试这一假设与强大的新血管壁磁共振成像技术结合磁共振成像对比 标记颅内动脉粥样硬化中的巨噬细胞，这将允许识别创新的 颅内动脉粥样硬化卒中风险的生物标志物和未来研究的潜在治疗靶点。通过 为了实现以下具体目标，申请人将测试其假设并收集临床试验数据， 降低颅内动脉粥样硬化的复发性卒中风险（将在K23期间的R 01申请中提出 奖励期）。具体目标1将检验以下假设： 巨噬细胞，将在最近引起中风的颅内动脉粥样硬化的动脉中看到。具体 目的2将检验一个假设，即颅内动脉粥样硬化和ferumoxytol标记的动脉 巨噬细胞将具有由颅内动脉粥样硬化引起的动脉狭窄的进展， 一年期。具体目标3将检验颅内动脉粥样硬化动脉和 ferumoxytol标记的巨噬细胞在一年内会有更多的中风。 这项研究是有意义的，因为颅内动脉粥样硬化研究不足，需要新的 采取措施降低其风险。这项研究是创新的，因为它结合了先进的成像技术， 技术（血管壁MRI）和巨噬细胞特异性MRI造影剂ferumoxytol的新用途，以提供 从颅内动脉粥样硬化中了解卒中机制的多模式治疗 使用针对巨噬细胞的药物进行治疗。