Mechanisms of Neural Repair in White Matter Stroke

描述(申请人提供)：中风是导致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著增加，这将促进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集中在大动脉或皮质梗塞的实验模型上。这些模型在大脑皮层、纹状体或两者都会产生中风。然而，人类高达25%的中风发生在白质中。白质中风是严重残疾的一个来源，并可累积导致血管性痴呆，这是痴呆症的第二大原因。多发性硬化症模型中白质损伤的研究表明，神经胶质前体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质卒中患者脑白质修复和恢复的可能性的研究。这一局限性是由于缺乏有效的脑白质中风动物模型。我们最近开发了一种小鼠前肢运动皮质下白质皮质下卒中的模型，该模型模拟了人类这种疾病的许多方面。这一小鼠模型表明，白质卒中会产生一个少突胶质细胞完全损伤和死亡的区域，但也会产生一个演变中的部分损伤、少突胶质细胞前体细胞的扩张和新的少突胶质细胞群体。中风周围的这一过程表明中风的部分脑白质修复。这项资助的目标是确定皮质下/白质中风中白质修复的细胞和分子机制，将这些发现推广到老年动物，并操纵这些系统以促进白质修复和功能恢复。拟议的研究将使用多学科方法，包括遗传细胞命运定位、白质功能的电生理表征、小鼠运动恢复和激光捕捉的行为学研究以及白质卒中神经胶质前体反应的遗传分析。这些研究将在没有脑白质修复数据的中风领域，建立对神经胶质前体反应和白质修复的详细细胞和分子理解，然后操纵候选分子系统，以确定它们在这种疾病的修复和恢复中的因果作用。 与公共卫生相关：脑部连接区域的中风，被称为大脑“白质”，是中风的一种常见亚型。然而，关于这种疾病的损伤和脑修复机制的研究很少。这项资助中的研究确定了白质中风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.