Mechanisms of White Matter Repair in Subcortical White Matter Ischemia

项目概要/摘要 白色物质缺血是一种进行性血管疾病，其导致局灶性神经功能缺损，累积至 导致痴呆症，并加速阿尔茨海默病的病理。术语白色物质缺血或白色 基于成像的物质高强度对应于几种疾病病理，包括进行性的 血脑屏障破坏、小的局灶性中风和动脉末端灌注不足。白色物质缺血是 与年龄密切相关：在80岁时，我们所有人在MRI上都会有白色高信号。尽管作出了重大的 炎症性白色疾病（如多发性硬化）中白色修复机制的临床前研究 硬化），关于脑白色物质如何响应白色物质缺血的信息很少，并且可能 启动神经修复本研究利用小鼠白色物质缺血模型， 以及皮质下白色物质中小血管的进行性损伤，以确定 白色物质修复。这些研究表征了介导这一过程的候选分子系统， 在白色缺血和修复和恢复期间的神经元网络功能。这些研究将决定 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、转基因细胞命运作图、光遗传学和静息状态MRI研究，以及 病毒获得和功能丧失方法。这项工作的结果将是确定新的分子靶点 对于白色脑缺血的神经修复，了解导致脑缺血的神经网络功能， 并开发一种白色物质修复和恢复的成像生物标志物 缺血

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.