Project Summary Cerebral microvascular disease (CMD) causes white matter injury and is a major contributor of the vascular contributions to cognitive impairment and dementia (VCID), including as the most common co-morbidity to clinical Alzheimer?s Disease. Chronic vascular risk factors such as obesity accelerate the progression of CMD by primarily damaging brain endothelial cells. Risk factor-induced changes in cerebral endothelial cells contribute to an increased risk of dementia. The molecular changes in cerebral endothelial cells caused by chronic cerebrovascular risk factors remain unknown yet are critical to designing therapies to prevent and repair ischemic white matter lesions thereby lessening the burden of VCID. We propose that a central mechanism of CMD progression is dysregulated signaling in brain endothelial cells damaged by chronic vascular risk factors. Using endothelial cell-specific transcriptional profiling, we show that chronic endothelial injury resulting from obesity results in abnormal vascular expression of an interleukin/chemokine signaling pathway. This molecular pathway results in dysregulated vascular-oligodendrocyte progenitor cell (OPC) signaling. OPCs are a critical progenitor cell population in brain white matter that respond to injury and are responsible for remyelination. Preliminary data demonstrate that chronically injured endothelial cells up-regulate IL-17 receptor b (IL-17Rb) and its effector chemokine CXCL5. Though many inflammatory pathways may play a role in brain ischemia, we show that this is the major inflammatory pathway that is active in endothelial cells injured by this chronic vascular risk factor. Critically, we further demonstrate that endothelial expression of CXCL5 results in the chemotaxis of OPCs to the vasculature, limiting their ability to remyelinate after a focal white matter ischemic lesion. Using gain and loss of function studies at the in vitro, in vivo, and functional levels after stroke, we will dissect the molecular pathways involved in dysregulated vascular-OPC signaling and identify a role for chemokine signaling in regulating white matter injury underlying VCID. Studies in Aim 1 will use an in vitro conditioned medium paradigm to identify the precise signaling mechanisms in endothelial cells that promote CXCL5 expression while identifying the necessary receptors on OPCs that regulate migration and differentiation. In Aim 2, we will broadly determine the role of chemokine receptor activation on the ability of OPCs to differentiate and remyelinate after stroke using CXCR2 knockout and small molecule antagonism. Finally, we will show in Aim 3 that blocking the expression of CXCL5 in white matter endothelia can reduce cognitive and motor impairment associated with focal white matter stroke by promoting remyelination within the peri-infarct tissue adjacent to stroke. Together, these studies establish new molecular mechanisms for the vascular regulation of remyelination as critical to the pathogenesis of CMD and establish a new therapeutic target for VCID.