Mechanisms of Recovery After White Matter Injury

过去十年神经科学的主要发现之一是成年哺乳动物的大脑是可塑性的， 尤其是在脑损伤之后。在灰质中所谓的神经血管壁龛中，细胞-细胞之间的信号传递 大脑内皮细胞和神经前体细胞维持正在进行的神经发生和 可能有助于大脑重塑/修复的血管生成。然而，白质的机制 可塑性在很大程度上仍然未知。在这里，我们假设一个相应的白色“少血管生态位” 物质是少突胶质细胞-内皮营养偶联所必需的，它介导了少突胶质细胞的形成和 脑白质重塑/修复的血管生成。 在目标1中，我们建议使用细胞培养来证明少突胶质细胞和 脑损伤后脑内皮细胞发生改变。我们还将检验这样一个假设，即条件化媒体 从少突胶质细胞改变白质损伤后的小胶质细胞表型(与项目合作 1)。 在目标2中，我们将使用细胞和脑片培养来证明血管内皮生长因子和基质金属蛋白酶-9是关键 少突胶质细胞-内皮细胞相互作用促进血管生成和少突胶质细胞生成的介体 脑白质损伤后。我们还将测试Rho-Kinase途径可能是一个有希望的假说。 促进白质重塑的目标(与项目3合作)。 在目标3中，我们将使用白质损伤的小鼠模型(慢性脑低灌注，局灶性 脱髓鞘和局灶性卒中)，以证实少突胶质细胞和 血管内皮细胞有助于损伤后白质的可塑性。成像实验和行为学 评估将分别由核心A和核心B提供支持。 白质损害是几种中枢神经系统疾病的临床重要方面，包括中风和 血管性痴呆。然而，与灰质的机制相比，白质的病理生理学 研究相对较少，对此了解较少。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质重塑的新机制 受伤后。解剖这些细胞-细胞通路可能会为慢性前列腺癌患者带来新的治疗方法。 影响脑白质的紊乱。

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.