Treatment Targets for Inflamed Intracranial Atherosclerosis on Vessel Wall MRI

项目概要/摘要 这是 Adam de Havenon 博士的 K23 奖项申请，他是一名神经科医生和年轻研究员，致力于研究 以患者为导向的颅内动脉粥样硬化引起的缺血性脑卒中的临床研究。 K23 奖将 为他提供获得三个关键职业发展领域关键技能的方法：1）生物统计学和 临床试验设计，2) 动脉粥样硬化生物学和 3) 转化 MRI 研究。通过获取这些 技能，德哈农博士将实现他的职业目标，成为一名独立调查员，能够弥合 血管神经病学的神经影像研究和临床试验学科。为了实现这一目标，德博士 哈维农组建了博士的指导团队。 Dennis Parker（主要导师），一位 MRI 物理学家 脑血管系统神经影像评估方面的专业知识，以及 Jennifer Majersik（共同导师）， 具有中风流行病学和临床试验设计专业知识的神经科医生。补充他们的是四人 拥有生物统计学、临床试验、颅内动脉粥样硬化和 MRI 权威的咨询委员会。 颅内动脉粥样硬化是世界上最常见的中风原因，并且发病率最高 中风复发。根据最近的证据和他自己的初步数据，德哈农博士的核心 假设认为颅内动脉粥样硬化引起的缺血性中风是由于巨噬细胞介导的脆弱性所致。 我们将利用强大的新型血管壁 MRI 技术结合 MRI 对比来检验这一假设 标记颅内动脉粥样硬化中的巨噬细胞，这将有助于识别创新的 颅内动脉粥样硬化中风风险的生物标志物和未来研究的潜在治疗目标。由 为了实现以下具体目标，申请人将检验其假设并收集临床试验数据，以 降低颅内动脉粥样硬化复发性中风风险（将在 K23 期间的 R01 应用中提出） 奖励期限）。具体目标 1 将检验以下假设：ferumoxytol（标记的 MRI 对比剂） 巨噬细胞，可以在最近引起中风的颅内动脉粥样硬化的动脉中看到。具体 目标 2 将检验以下假设：患有颅内动脉粥样硬化且带有阿莫西托标记的动脉 巨噬细胞会在一段时间内使颅内动脉粥样硬化引起的动脉狭窄进展。 为期一年。具体目标 3 将检验以下假设：患有颅内动脉粥样硬化的动脉和 ferumoxytol 标记的巨噬细胞在一年内会发生更多的中风。 拟议的研究意义重大，因为颅内动脉粥样硬化尚未得到充分研究，需要新的研究 降低其风险的方法。拟议的研究具有创新性，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 对比 ferumoxytol 的新用途，以提供 多模式深入了解可治疗的颅内动脉粥样硬化中风机制 使用针对巨噬细胞的药物进行治疗。

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.