Mechanisms of Neural Repair in White Matter Stroke

描述（由申请人提供）：中风是成人残疾的主要原因。随着人口老龄化，中风的发病率预计将显着增加，促进了对这种疾病的修复和恢复机制的密集研究。然而，这项研究的重点几乎完全指向大动脉或皮质梗死的实验模型。这些模型在皮层、纹状体或两者中产生中风。然而，高达25%的人类中风发生在白色物质中。白色物质中风是严重残疾的一个来源，并且可以累积引起血管性痴呆，这是痴呆的第二大原因。在多发性硬化模型中对白色物质损伤的研究表明，胶质祖细胞可以对损伤做出反应，并启动修复甚至恢复的过程。目前还没有关于皮质下或白色物质卒中中白色物质修复和恢复的可能性的研究。这种局限性是由于缺乏有效的白色物质中风动物模型。我们最近在小鼠前肢运动皮层下的白色物质中开发了一种皮层下中风模型，该模型模拟了人类这种疾病的许多方面。该小鼠模型表明，白色脑卒中产生了少突胶质细胞的完全损伤和死亡区，但也产生了进化的部分损伤、少突胶质细胞祖细胞的扩增和新的少突胶质细胞群的周围。中风周围的这一过程表明中风中部分白色物质修复。本基金的目标是确定皮质下/白色物质中风中白色物质修复的细胞和分子机制，将这些发现扩展到老年动物，并操纵这些系统以增强白色物质修复和功能恢复。拟议的研究将采用多学科方法，包括遗传细胞命运作图、白色物质功能的电生理学表征、小鼠运动恢复的行为学研究以及白色物质卒中中胶质祖细胞反应的激光捕获和遗传分析。这些研究将在没有白色物质修复数据的中风领域，发展对胶质祖细胞反应和白色物质修复的详细细胞和分子理解，然后操纵候选分子系统以确定其在这种疾病的修复和恢复中的因果作用。 公共卫生相关性：脑内携带连接的区域（称为脑“白色物质”）的中风是中风的常见亚型。然而，很少有人研究这种疾病的损伤和脑修复机制。本研究旨在确定白色物质卒中修复和恢复的分子和细胞机制。

DESCRIPTION (provided by applicant): Stroke is the leading cause of adult disability. As the population ages, stroke incidence is expected to markedly increase, fostering an intense research focus on mechanisms of repair and recovery in this disease. However, this research focus has been directed almost entirely to experimental models of large artery or cortical infarcts. These models produce strokes in cortex, striatum or both. However, up to 25% of all strokes in humans occur in white matter. White matter strokes are a source of significant disability and can accumulate to cause vascular dementia, the second leading cause of dementia. Studies in white matter injury in models of multiple sclerosis indicate that glial progenitor cells can respond to the injury and initiate a process of repair and even recovery. There have been no studies of the possibility of white matter repair and recovery in subcortical or white matter stroke. This limitation has been due to lack of an effective animal model of white matter stroke. We have recently developed a model of subcortical stroke in white matter below the mouse forelimb motor cortex that models many aspects of this disease in humans. This mouse model indicates that white matter stroke produces a zone of complete damage and death of oligodendrocytes, but also a surround of evolving partial damage, an expansion of oligodendrocyte progenitor cells, and new populations of oligodendrocytes. This process in the stroke surround suggests a partial white matter repair in stroke. The goals of this grant are to determine the cellular and molecular mechanisms of white matter repair in subcortical/white matter stroke, to extend these findings to aged animals, and to manipulate these systems to enhance white matter repair and functional recovery. The proposed studies will use a multi-disciplinary approach of genetic cell fate mapping, electrophysiological characterization of white matter function, behavioral study of mouse motor recovery and laser capture and genetic analysis of glial progenitor responses in white matter stroke. These studies will take a field of stroke in which there is no data on white matter repair, develop a detailed cellular and molecular understanding of glial progenitor responses and white matter repair, and then manipulate candidate molecular systems to determine their causal role in repair and recovery in this disease. PUBLIC HEALTH RELEVANCE: Stroke in the areas of the brain that carry connections, termed cerebral "white matter", is a common subtype of stroke. However, there have been few studies of the mechanisms of damage and brain repair in this disease. The studies in this grant determine the molecular and cellular mechanisms of repair and recovery in white matter stroke.