The role of CD147 in ischemic inflammation and brain injury

描述(申请人提供)：这份R01申请旨在研究CD147在卒中诱导的外周免疫功能障碍和卒中病理中的新作用。最近的研究，包括我们自己的研究，支持一个重要的概念，即卒中引起的外周免疫功能障碍不仅使患者容易发生卒中后感染(尤其是肺炎)，而且通过加剧和维持缺血后脑内的炎症反应而导致继发性脑损伤。脾已成为中风后调节外周免疫反应的新靶点。基于初步研究部分讨论的新发现，我们提出了中心假设，即CD147是脾对局灶性脑缺血反应的新的关键调节因子，并在卒中后继发性脑损伤中起重要作用。具体地说，我们认为脾单核细胞通过一种新的CD147机制在卒中介导的脑损伤中发挥关键作用。特定目的1将验证CD147在缺血性炎症和脑损伤中起重要作用的假设，从而治疗性阻断CD147在缺血性中风中提供神经血管保护。目的1a：我们将研究CD147的治疗靶点是否在缺血性中风中起到神经血管保护作用。抗CD147功能阻断抗体将在临床相关时间点静脉注射。目的1b：探讨CD147参与卒中损伤的细胞和分子机制，重点观察卒中后脑内白细胞的浸润、血脑屏障的破坏和脾的炎性激活。目的1c：我们将确定CD147的治疗靶点是否对卒中后的功能恢复有长期的有益影响。特异性目标2将验证CD147是脾免疫反应的关键介体，并通过脾炎性单核细胞在缺血性中风中起作用的假设。目的：探讨CD147在TMCAO小鼠脾组织中的细胞类型特异性表达及其在卒中后脾免疫细胞(尤其是单核细胞、T细胞)炎症激活中的作用。目的2b：将脾单核细胞过继移植到去脾小鼠体内，以确定炎性单核细胞是否在卒中损伤中起重要作用。为了选择性地靶向脾单核细胞上的CD147，将使用siRNA敲除技术。目的2c：我们将确定CD147靶向治疗卒中后脾萎缩和卒中后感染的效果。这些研究将揭示CD147在脾的免疫反应中的新作用以及对脑缺血的贡献，这些发现可能对开发新的中风治疗方法具有潜在的意义。

DESCRIPTION (provided by applicant): This R01 application aims to investigate novel roles of CD147 in stroke-induced peripheral immune dysfunction and stroke pathology. Recent studies, including our own, favor an important notion that stroke-induced peripheral immune dysfunction not only predisposes patients to post-stroke infections (particularly pneumonia) but also contributes to secondary brain damage by exacerbating and perpetuating inflammatory response in the post-ischemic brain. The spleen has emerged as a novel target that mediates the peripheral immune response after stroke. Based on the novel findings discussed in the Preliminary Studies section, we propose the central hypothesis that CD147 acts as a novel key regulator of the splenic response to focal cerebral ischemia and that contributes importantly to secondary brain damage after stroke. Specifically, we propose that spleen monocytes play a critical role in stroke- mediated brain injury through a novel CD147 mechanism. Specific Aim 1 will test the hypothesis that CD147 contributes importantly to ischemic inflammation and brain injury and thus therapeutic blockade of CD147 provides neurovascular protection in ischemic stroke. Aim 1a: We will investigate whether therapeutic targeting of CD147 provides neurovascular protection in ischemic stroke. Anti-CD147 function-blocking antibodies will be given by intravenous injection at clinically relevant time points. Aim 1b: We will investigate the cellular and molecular mechanisms by which CD147 contributes to stroke injury, with a focus on examining brain leukocyte infiltration, BBB disruption, and the splenic inflammatory activation after stroke. Aim 1c: We will determine whether therapeutic targeting of CD147 has long-term beneficial effects on functional recovery after stroke. Specific Aim 2 will test the hypothesis tha CD147 is a key mediator of the spleen's immune response and contribution to ischemic stroke through spleen inflammatory monocytes. Aim 2a: We will determine the cell-type specific expression of CD147 in the spleens of mice subjected to tMCAO and the role of CD147 in inflammatory activation of splenic immunocytes (particularly monocytes, T cells) after stroke. Aim 2b: By adoptive transfer of spleen monocytes into splenectomized mice, we will determine whether spleen inflammatory monocytes contribute importantly to stroke injury. To selectively target CD147 on spleen monocytes, siRNA knockdown technique will be used. Aim 2c: We will determine the effects of therapeutic targeting of CD147 on stroke-induced splenic atrophy and poststroke infections. These studies will reveal novel roles of CD147 in the spleen's immune response and contribution to cerebral ischemia, and the findings may have potential implications for developing novel treatments for stroke.