Mechanisms of Neural Repair in White Matter Stroke

描述（由申请人提供）：中风是导致成人残疾的主要原因。随着人口的老龄化，脑卒中的发病率预计将显著增加，促进了对这种疾病的修复和恢复机制的强烈研究。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、纹状体或两者都产生中风。然而，高达25%的人类中风发生在白质中。白质中风是严重残疾的一个来源，积累起来会导致血管性痴呆，这是痴呆症的第二大原因。对多发性硬化症白质损伤模型的研究表明，神经胶质祖细胞可以对损伤作出反应，并启动修复甚至恢复过程。目前还没有关于皮层下或白质中风中白质修复和恢复的可能性的研究。这一限制是由于缺乏有效的白质脑卒中动物模型。我们最近在小鼠前肢运动皮层下的白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，白质卒中产生少突胶质细胞的完全损伤和死亡区，但也产生进化的部分损伤，少突胶质细胞祖细胞的扩增和新的少突胶质细胞群。卒中周围的这一过程表明卒中时白质部分修复。该基金的目标是确定皮层下/白质中风中白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质修复和功能恢复。该研究将采用多学科的方法，包括遗传细胞命运定位、白质功能的电生理特征、小鼠运动恢复和激光捕获的行为研究以及白质中风中神经胶质祖细胞反应的遗传分析。这些研究将在没有白质修复数据的中风领域开展，对神经胶质祖细胞反应和白质修复进行详细的细胞和分子理解，然后操纵候选分子系统来确定它们在这种疾病的修复和恢复中的因果作用。

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.