Regulation of the microglial response to stroke.

描述（由申请人提供）：炎症过程在卒中的病理生理学中具有重要作用。一个关键的初始事件是快速激活常驻免疫细胞，主要是小胶质细胞。该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受到涉及神经元-胶质细胞通讯的严格控制机制的控制。CD 200是一个重要的，但未充分研究的小胶质细胞活化调节。CD 200在多种细胞类型上表达，包括内皮细胞和神经元。神经元CD 200通过与小胶质细胞上的CD 200受体（CD 200 Rs）相互作用诱导抑制信号，从而减少损伤诱导的炎症。CD 200-CD 200 R信号传导的破坏在神经炎症模型中加重了损伤，但该信号传导途径在卒中中尚未得到充分研究。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CD 200对小胶质细胞的正常抑制性约束，并且这在老年大脑中进一步加剧。我们将利用一个完善的中风实验模型，大脑中动脉闭塞（MCAO），以确定是否CD 200信号转导被激活后，缺血性损伤（目标1）和操纵这一信号转导途径，以确定对梗死面积的影响（目标2）。本建议的主要目标是确定是否CD 200信号转导改变中风的实验模型，这种激活的时间过程，以及它在老年大脑中是否有所不同。

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.