Mechanisms of White Matter Repair in Subcortical White Matter Ischemia

项目摘要/摘要 白质缺血是一种进行性血管疾病，导致局灶性神经功能障碍，积累到 导致痴呆症，加速阿尔茨海默病的病理过程。术语白质缺血或白色 根据成像，物质高密度对应于几种疾病病理，包括进行性疾病 血脑屏障破坏，局灶性卒中和末梢动脉低灌注率。脑白质缺血是 与年龄密切相关：在80岁时，我们所有人的MRI上都会有白质高信号。尽管有大量的 炎症性脑白质病白质修复机制的临床前研究 硬化症)，关于大脑白质如何对白质缺血做出反应的信息很少，而且可能 启动神经修复。这项资助利用了小鼠的白质缺血模型，这种模型会产生弥漫性 以及皮质下白质小血管的进行性损害，以确定其机制 脑白质修复。这些研究表征了参与这一过程的候选分子系统，并确定了 神经元网络在脑白质缺血及修复和恢复过程中的作用。这些研究将确定 年龄对这些过程的影响。这笔赠款将使用一个创新的技术平台，包括 新开发的小鼠模型，转基因细胞命运图，光遗传和静息状态磁共振研究，以及 病毒式获得和丧失功能的方法。这项工作的结果将是识别新的分子靶标 对于白质缺血的神经修复，发展对神经网络功能的理解 这种疾病的行为缺陷，并开发一种白质修复和恢复的成像生物标记物 缺血症。

Project Summary/Abstract White matter ischemia is a progressive vascular disease that leads to focal neurological deficits, accumulates to cause dementia, and accelerates the pathology of Alzheimer's Disease. The term white matter ischemia or white matter hyperintensity, based on imaging, corresponds to several disease pathologies, including progressive blood brain barrier breakdown, small focal strokes and end-arterial hypoperfusion. White matter ischemia is strongly age-associated: at age 80 all of us will have white matter hyperintensities on MRI. Despite substantial pre-clinical study of mechanisms of white matter repair in inflammatory white matter disease (such as multiple sclerosis), there is little information on how cerebral white matter responds to white matter ischemia, and may initiate neural repair. This grant utilizes a model of white matter ischemia in the mouse, which produces diffuse and progressive damage from the small vessels in the subcortical white matter, to determine the mechanisms of white matter repair. The studies characterize candidate molecular systems that mediate this process and identify neuronal network function in white matter ischemia and during repair and recovery. The studies will determine the effects of age on these processes. This grant will use an innovative platform of technologies, including a newly developed mouse model, transgenic cellular fate-mapping, optogenetic and resting state MRI studies, and viral gain and loss of function approaches. The outcome of this work will be to identify novel molecular targets for neural repair in white matter ischemia, develop an understanding of the neuronal network function that leads to behavioral deficits in this disease, and develop an imaging biomarker for repair and recovery in white matter ischemia.