The Role of CD147 in Ischemic Inflammation and Brain Injury

描述（由申请人提供）：本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，即中风引起的外周免疫功能障碍不仅使患者易患中风后感染（特别是肺炎），而且还通过加剧和延续缺血后大脑的炎症反应，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。基于在“初步研究”部分中讨论的新发现，我们提出了CD147作为局灶性脑缺血脾反应的一种新的关键调节因子，并在脑卒中后继发性脑损伤中起重要作用的中心假设。具体来说，我们提出脾脏单核细胞通过一种新的CD147机制在脑卒中介导的脑损伤中发挥关键作用。特异性目的1将验证CD147在缺血性炎症和脑损伤中起重要作用的假设，因此治疗性阻断CD147可在缺血性卒中中提供神经血管保护。目的1a：我们将研究靶向治疗CD147是否在缺血性卒中中提供神经血管保护。在临床相关时间点静脉注射抗cd147功能阻断抗体。目的1b：我们将研究CD147促进脑卒中损伤的细胞和分子机制，重点研究脑卒中后脑白细胞浸润、血脑屏障破坏和脾炎症激活。目的1c：我们将确定靶向治疗CD147是否对脑卒中后功能恢复有长期的有益影响。特异性目的2将验证CD147是脾脏免疫反应的关键介质，并通过脾脏炎症单核细胞参与缺血性卒中。目的2a：我们将测定经tMCAO处理的小鼠脾脏中CD147的细胞类型特异性表达，以及CD147在中风后脾免疫细胞（特别是单核细胞、T细胞）炎症激活中的作用。目的2b：通过脾单核细胞过继移植脾切除小鼠，我们将确定脾炎性单核细胞是否在脑卒中损伤中起重要作用。为了选择性地靶向脾脏单核细胞上的CD147，将使用siRNA敲低技术。目的2c：我们将确定靶向治疗CD147对脑卒中诱导的脾萎缩和脑卒中后感染的影响。这些研究将揭示CD147在脾脏免疫反应和脑缺血中的新作用，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.