Oligodendrocyte Progenitor Cell Response to White Matter Stroke

项目总结/摘要 白色物质中风是一种进行性血管疾病，可导致神经功能缺损，并可导致痴呆。 它产生一个细胞死亡和轴突破坏的区域（“梗死”），并诱导一种反应性免疫应答。 星形胶质细胞和少突胶质细胞前体细胞。在70%的临床研究中，白色物质中风从 预先存在的损伤进入邻近的白色物质（“梗塞周围”区域）， 连接，造成严重残疾。目前，我们对白色物质修复的了解主要来自于 来自对白色物质的非中风损伤如多发性硬化症（MS）的研究。髓鞘再生有限 在MS中通过少突胶质祖细胞（OPC）反应，其中OPC增殖、分化成 少突胶质细胞和髓鞘再生轴突。OPCs在白色物质卒中的梗死周围区域增殖，但 与MS不同，它们似乎不成熟为髓鞘生成少突胶质细胞。这项研究将利用最近 开发了弥漫性白色脑中风的小鼠模型，该模型会从小血液中产生进行性损伤 胼胝体血管该模型产生更大的病变，并且更接近地模拟晚期、慢性、 人类白色物质中风的阶段。在目标1中，我将绘制白色后的OPC反应和髓鞘形成事件。 使用新的病毒和转基因方法确定OPCs的细胞命运结果。在目标2中， 我将确定候选基因诱导的OPC分化在体内白色物质修复中的作用。这些 基因被鉴定为在中风诱导的OPCs中高度改变，以及在中风诱导的OPCs中促进OPC分化。 体外这项工作的结果将是确定新的分子靶点神经修复和功能恢复 在白色物质中风。

Project Summary/Abstract White matter stroke is a progressive vascular disease that leads to neurological deficits and can cause dementia. It produces an area of cell death and axonal disruption (the “infarct”) and induces a response of reactive astrocytes and oligodendrocyte precursors cells. In 70% of clinical studies, white matter strokes expand from preexisting lesions into adjacent white matter (the “peri-infarct” region) further damaging and disrupting neuronal connections, causing substantial disability. Currently, what is largely known about white matter repair is derived from studies in non-stroke injuries of white matter such as multiple sclerosis (MS). Limited remyelination occurs in MS through an oligodendrocyte progenitor cell (OPC) response in which OPCs proliferate, differentiate into oligodendrocytes, and remyelinate axons. OPCs proliferate in the peri-infarct region in white matter stroke, but unlike in MS, they do not appear to mature into myelinating oligodendrocytes. This study will utilize a recently developed mouse model of diffuse white matter stroke that produces progressive damage from the small blood vessels in the corpus callosum. This model produces a larger lesion and more closely mimics advanced, chronic stages of human white matter stroke. In aim 1, I will map the OPC response and myelination events after white matter stroke and determine cell fate outcomes of OPCs using novel viral and transgenic approaches. In aim 2, I will determine the role of OPC differentiation induced by candidate genes in white matter repair in vivo. These genes were identified to be highly altered in stroke-induced OPCs as well as to promote OPC differentiation in vitro. The outcome of this work will be to identify novel molecular targets for neural repair and functional recovery in white matter stroke.