Regulation of the microglial response to stroke.

描述（由申请人提供）：炎症过程在中风的病理生理中起着重要作用。一个关键的初始事件是常驻免疫细胞的快速激活，主要是小胶质细胞。这种细胞群是限制中风损伤的新治疗方法的重要靶点。小胶质细胞的激活通常被严格控制的机制所控制，包括神经元-胶质细胞的通讯。CD200是一种重要的小胶质细胞激活调节因子，但尚未得到充分研究。CD200在多种细胞类型上表达，包括内皮细胞和神经元。神经元CD200通过与CD200受体（CD200Rs）相互作用诱导抑制信号，减少小胶质细胞损伤性炎症。在神经炎症模型中，CD200-CD200R信号通路的破坏会加重损伤，但这一信号通路尚未在卒中中得到很好的研究。衰老与小胶质细胞数量和激活状态的增加有关。我们假设中风降低了神经元CD200对小胶质细胞的正常抑制约束，并且这在老年大脑中进一步加剧。我们将利用一个完善的脑卒中实验模型，大脑中动脉闭塞（MCAO），来确定CD200信号是否在缺血损伤后被激活（目的1），并操纵这一信号通路来确定对梗死面积的影响（目的2）。这项提议的主要目的是确定CD200信号是否在中风的实验模型中被改变，这种激活的时间过程，以及它是否在老年大脑中有所不同。

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. PUBLIC HEALTH RELEVANCE: 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.