Mechanisms of Recovery After White Matter Injury

点击翻译按钮获取中文摘要

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.