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Mechanisms of White Matter Repair in Subcortical White Matter Ischemia

皮质下白质缺血的白质修复机制

基本信息

批准号：
10601085
负责人：
Stanley Thomas Carmichael
金额：
$ 42.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601085
关键词：
Acceleration Age Alzheimer&apos s disease pathology Behavioral Bioinformatics Biological Markers Blood - brain barrier anatomy Brain Brain region Calcium Candidate Disease Gene Cell physiology Cerebrum DIF factor Data Dementia Diffuse Diffusion Disease Focal Neurologic Deficits Gene Expression Profiling Genes Goals Grant Human Image In Vitro Inflammatory Ischemia Label Magnetic Resonance Imaging Maps Mediating Modeling Molecular Molecular Target Multiple Sclerosis Mus Neurons Outcome Pathology Pre-Clinical Model Process Proliferating Public Health Recovery Reporter Genes Rest Role Sensory Stroke Structure System Testing Transgenic Organisms Vascular Diseases Viral White Matter Disease White Matter Hyperintensity Work age effect aged gain of function hypoperfusion imaging biomarker in vivo innovation loss of function motor impairment mouse model neural initiation neural repair new therapeutic target novel oligodendrocyte precursor optogenetics preclinical study precursor cell regenerative repaired response technology platform white matter white matter injury

项目摘要

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.

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。