Regulation of the microglial response to stroke.

描述(申请人提供)：炎症过程在中风的病理生理学中起着重要的作用。最初的一个关键事件是常驻免疫细胞的快速激活，主要是小胶质细胞。这些细胞群是限制中风损害的新治疗方法的重要靶点。小胶质细胞的激活通常由涉及神经元-神经胶质通讯的严格控制的机制来控制。CD200是小胶质细胞激活的重要调节因子，但研究较少。CD200表达于多种细胞类型，包括内皮细胞和神经元。神经元CD200通过与小胶质细胞上的CD200受体(CD200Rs)相互作用而诱导抑制信号，从而减轻损伤诱导的炎症反应。在神经炎症模型中，CD200-CD200R信号通路的破坏加重了损伤，但这一信号通路在卒中中尚未得到很好的研究。衰老与小胶质细胞数量和激活状态的增加有关。我们假设，中风减少了神经元CD200对小胶质细胞的正常抑制限制，这在老年大脑中进一步加剧。我们将利用一个成熟的中风实验模型，大脑中动脉闭塞(MCAO)，确定CD200信号在缺血损伤后是否被激活(目标1)，并操纵这一信号通路来确定对梗塞面积的影响(目标2)。这项建议的主要目标是确定CD200信号在中风实验模型中是否改变，这种激活的时间进程，以及在老年脑中是否不同。

DESCRIPTION (provided by applicant): 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.