Inflammatory processes have a fundamental role in the pathophysiology of stroke. A key initial event is the rapid activation of resident immune cells, primarily the microglia. This cell population is an important target for new therapeutic approaches to limit stroke damage. Activation of microglia is normally held in check by strictly controlled mechanisms involving neuronal-glial communication. CD200 is an important, but understudied regulator of microglia activation. CD200 is expressed on a variety of cell types, including endothelium and neurons. Neuronal CD200 induces an inhibitory signal by interacting with CD200 receptors (CD200Rs) on microglia reducing injury-induced inflammation. Disruption of CD200-CD200R signaling aggravates injury in models of neuroinflammation but this signaling pathway has not been well investigated in stroke. Aging is associated with an increase in the number and activation state of microglia. We hypothesize that stroke decreases the normal inhibitory constraints of neuronal CD200 on microglia and that this is further exacerbated in the aged brain. We will utilize a well-established experimental model of stroke, middle cerebral artery occlusion (MCAO), to determine if CD200 signaling is activated after an ischemic insult (Aim 1) and manipulate this signaling pathway to determine the effects on infarct size (Aim 2).The main goal of this proposal is to determine if CD200 signaling is altered in experimental models of stroke, the time- course of this activation, and if it differs in the aged brain.
There is considerable evidence that inflammation plays a major role in outcomes from clinical and experimental stroke. Microglia, the resident immune cell of the brain, are a key player in stroke- induced damage. As stroke is now the number one cause of disability, new treatments targeting microglial regulation should be explored.
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