Treatment Targets for Inflamed Intracranial Atherosclerosis on Vessel Wall MRI

项目摘要/摘要 这是亚当·德·哈维农博士的K23奖项申请，他是一名神经学家，也是一名年轻的研究人员 以患者为中心的颅内动脉粥样硬化性缺血性卒中的临床研究。一个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手段：1)生物统计学和 临床试验设计，2)动脉粥样硬化的生物学和3)翻译MRI研究。通过获得这些 技能，德·哈维农博士将实现他的职业目标，成为一名独立的调查员，能够在 血管神经学的神经影像研究和临床试验的学科。为了实现这一目标，德博士 哈维农组建了丹尼斯·帕克博士(主要导师)的指导团队，他是一名核磁共振物理学家， 在脑血管系统的神经成像评估方面的专业知识，以及Jennifer Majersik(共同导师)， 在中风流行病学和临床试验设计方面具有专业知识的神经科医生。与他们相辅相成的是四个人 咨询委员会，在生物统计学、临床试验、颅内动脉粥样硬化和核磁共振方面拥有权威。 颅内动脉粥样硬化是世界上最常见的中风原因，也是中风发病率最高的 中风复发。根据最近的证据和他自己的初步数据，德·哈维农博士的中心 假设颅内动脉粥样硬化中的缺血性卒中是由于巨噬细胞介导的易损性。 我们将用强大的新血管壁核磁共振技术结合核磁共振对比剂来验证这一假设。 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 颅内动脉粥样硬化性中风风险的生物标志物和未来研究的潜在治疗目标。通过 为了达到以下具体目标，申请者将检验他的假设，并为临床试验收集数据 降低颅内动脉粥样硬化的再发中风风险(将在K23期间的R01应用中提出 获奖期)。特定目标1将测试阿魏酸甘油酯的假说，标记的MRI对比 巨噬细胞，可以在最近导致中风的颅内动脉粥样硬化的动脉中看到。特定的 目的2将验证这样的假设：患有颅内动脉粥样硬化和阿魏酸甲酯标记的动脉 巨噬细胞会使颅内动脉硬化引起的动脉狭窄进展超过一年。 一年期。具体目标3将检验这样一种假设，即患有颅内动脉粥样硬化和 在一年的时间里，标记了阿魏酸甘油的巨噬细胞会有更多的中风。 这项拟议的研究意义重大，因为对颅内动脉粥样硬化的研究还不够深入，需要新的 降低其风险的方法。这项拟议的研究具有创新性，因为它结合了先进的成像 技术(血管壁MRI)和巨噬细胞特异性MRI对比阿魏酸甘油的新用途，以提供 可治疗的颅内动脉粥样硬化性卒中机制的多模式洞察 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.