Mechanisms of Recovery After White Matter Injury

在过去的十年里，神经科学的主要发现之一是成年哺乳动物的大脑是可塑的， 尤其是在脑损伤之后在灰质中所谓的神经血管龛中， 大脑内皮和神经元前体细胞维持正在进行的神经发生的口袋， 血管生成可能有助于脑重塑/修复。然而，白色物质的机制 可塑性仍然是未知的。在此，我们假设相应的白色“少血管龛” 物质是少突胶质细胞-内皮营养偶联所必需的，其介导少突胶质细胞的发生， 血管生成用于白色物质重塑/修复。 在目标1中，我们提出使用细胞培养来显示少突胶质细胞和 脑损伤后脑内皮细胞发生改变。我们还将检验条件培养基 在白色物质损伤后改变小胶质细胞表型（与Project 1）。 在目标2中，我们将使用细胞和脑切片培养来证明VEGF和MMP-9是关键 介导少突胶质细胞-内皮细胞相互作用以促进血管生成和少突胶质细胞生成 白色物质损伤后。我们还将检验Rho激酶途径可能是一种有希望的 促进白色物质重塑的目标（与项目3合作）。 在目标3中，我们将使用白色物质损伤的小鼠模型（慢性脑灌注不足，局灶性脑缺血）。 脱髓鞘和局灶性中风），以证实少突胶质细胞和 内皮有助于损伤后白色物质的可塑性。成像实验和行为 评估将分别由核心A和核心B提供支持。 白色物质损伤是几种CNS疾病的临床重要方面， 血管性痴呆然而，与灰质机制相比，白色物质病理生理学 相对而言，研究不足，了解不多。我们提出的实验应该有助于定义一个 少突胶质细胞和脑内皮细胞调节白色物质重塑的新机制 伤后解剖这些细胞-细胞通路可能会为患有糖尿病的患者带来新的治疗方法。 影响白色物质的疾病。

One of the major findings in neuroscience in the past decade is that adult mammalian brain is plastic, especially after brain injury. In the so-called Neurovascular Niche in gray matter, cell-cell signaling between cerebral endothelium and neuronal precursor cells sustains pockets of ongoing neurogenesis and angiogenesis that may contribute to brain remodeling/repair. However, mechanisms for white matter plasticity are still mostly unknown. Here we hypothesize that a corresponding "Oligovascular Niche" in white matter is essential for oligodendrocyte-endothelial trophic coupling, which mediates oligodendrogenesis and angiogenesis for white matter remodeling/repair. In Aim 1, we propose to use cell cultures to show that the trophic coupling between oligodendrocytes and cerebral endothelium is altered after brain injury. We will also test the hypothesis that conditioned media from oligodendrocytes change the microglial phenotype after white matter injury (in collaboration with Project 1). In Aim 2, we will use cell and brain slice cultures to demonstrate that VEGF and MMP-9 are key mediators for the oligodendrocyte-endothelium interaction to promote angiogenesis and oligodendrogenesis after white matter injury. We will also test the hypothesis that Rho-kinase pathway can be a promissing target for promoting white matter remodeling (in collaboration with Project 3). In Aim 3, we will use mouse models of white matter injury (chronic cerebral hypoperfusion, focal demyelination, and focal stroke) to confirm that the trophic coupling between oligodendrocytes and endothelium contributes to white matter plasticity after injury. Imaging experiments and behavioral assessments will be supported by Core A and Core B, respectively. White matter damage is a clinically important aspect of several CNS diseases including stroke and vascular dementia. However, compared to mechanisms in gray matter, white matter pathophysiology remains relatively understudied and poorly understood. The experiments we propose should help define a novel mechanism by which oligodendrocytes and cerebral endothelial cells regulate white matter remodeling after injury. Dissecting these cell-cell pathways may lead to new therapeutic approaches for patients with disorders affecting white matter.