Microvascular Dysfunction in Cerebral Small Vessel Disease and Stroke

项目摘要/摘要 马克·埃瑟顿博士是麻省总医院(MGH)的血管神经学家，他的目标是成为 一位独立的临床研究科学家，擅长脑部小血管疾病的神经成像和 缺血性中风。这一建议的研究目的有三个方面：(1)阐明两者之间的关系 白质微血管功能和缺血组织结局；(2)提高对慢性疾病的认识 微血管功能障碍导致脑白质结构损伤和缺血性卒中结局； 早期血浆和神经影像指标与小鼠微血管功能的关系 血管疾病介导的缺血性卒中。拟议的研究充分利用了临床研究环境。 MGH卒中研究中心和两个独特的急性缺血性卒中数据库 敏感度对比MRI。目前的提案将分析这两个预期入选的急性缺血 卒中队列结合前瞻性、纵向研究，将功能神经成像与 血浆生物标志物分析。这项研究的成功完成将促进人们对白人 物质微血管功能障碍会导致卒中后脑梗塞的扩大和不良的功能预后。这 研究将对微血管的复杂相互关系产生重要的病理生理学见解 功能障碍和脑部小血管疾病，这可能有助于改善中风预防，风险 分层和个体化治疗以改善小血管疾病患者卒中后的预后。 这个应用程序提出了一个有重点的培训计划，并提供了具体的熟练程度衡量标准，以扩展Dr。 Etherton在全球缺血性卒中和弥散张量成像分析中的先前培训和研究活动 通过在(1)微血管神经成像方面提供必要的新的和正式的培训来保持白质的完整性 功能；(2)血脑屏障生物学基础；(3)实验设计/统计分析。 培训将包括个人和研究团队会议，与世界知名的 导师和合作者；神经成像、血脑屏障生物学、临床试验设计、 统计分析和负责任的研究；教育研讨会；和正式的神经成像培训 活动。他的培训计划利用了马蒂诺斯中心MGH世界级环境的资源 生物医学成像和哈佛大学公共卫生学院。主要导师纳塔莉亚博士的指导 Rost、共同导师Ona Wu博士、Cenk Ayata博士和Steven Greenberg博士，以及合作者Bruce Rosen博士， 陆汉章和Lori Chibnik将确保Etherton博士实现他的培训计划目标和里程碑。这个 本申请中概述的综合研究和培训计划将显著推进Etherton博士的 研究职业，并提供必要的技能，以追求以患者为导向的独立计划 研究脑小血管疾病和卒中微血管功能障碍的机制。

Project Summary/Abstract Dr. Mark Etherton is a Vascular Neurologist at Massachusetts General Hospital (MGH) whose goal is to become an independent, clinical research scientist with expertise in neuroimaging of cerebral small vessel disease and ischemic stroke. The research aims of this proposal are three-fold: (1) to elucidate the relationship between white matter microvascular function and ischemic tissue outcomes; (2) to advance knowledge on how chronic microvascular dysfunction contributes to white matter structural injury and ischemic stroke outcomes; and (3) to determine the relationship between early plasma and neuroimaging surrogates of microvascular function in small vessel disease-mediated ischemic stroke. The proposed study capitalizes on the clinical research environment of the MGH Stroke Research Center and two unique acute ischemic stroke databases with Dynamic Susceptibility Contrast MRI. The current proposal will analyze these two prospectively enrolled acute ischemic stroke cohorts in combination with a prospective, longitudinal study coupling functional neuroimaging with plasma biomarker analysis. Successful completion of this research study will advance knowledge on how white matter microvascular dysfunction contributes to infarct growth and poor functional outcomes after stroke. This research will yield important pathophysiological insights regarding the complex interrelations of microvascular dysfunction and cerebral small vessel disease, which may contribute to improved stroke prevention, risk stratification, and individualized therapies to improve post-stroke outcomes in patients with small vessel disease. This application proposes a focused training plan with specific measures of proficiency that extends Dr. Etherton’s prior training and research activities in ischemic stroke and diffusion tensor imaging analysis of global white matter integrity by providing necessary new and formal training in (1) neuroimaging of microvascular function; (2) fundamentals of blood-brain barrier biology; and (3) experimental design/statistical analysis. Training will involve individual and research team meetings with an interdisciplinary network of world-renowned mentors and collaborators; formal didactics in neuroimaging, blood-brain barrier biology, clinical trial design, statistical analysis, and responsible conduct of research; educational seminars; and formal neuroimaging training activities. His training plan leverages the resources of world-class environments at MGH, the Martinos Center for Biomedical Imaging, and the Harvard School of Public Health. The mentorship of primary mentor Dr. Natalia Rost, co-mentors Drs. Ona Wu, Cenk Ayata, and Steven Greenberg, along with collaborators Drs. Bruce Rosen, Hanzhang Lu, and Lori Chibnik will ensure Dr. Etherton achieves his training plan goals and milestones. The integrated research and training plans outlined in this application will significantly advance Dr. Etherton’s research career and provide the skillset necessary to pursue an independent program of patient-oriented research studying the mechanisms of microvascular dysfunction in cerebral small vessel disease and stroke.