The role of CD36 in ischemic inflammation and injury

缺血后炎症使缺血性卒中引发的脑损伤的发展复杂化。 CD 36是一种B类清道夫受体，对氧化低密度脂蛋白（oxLDL）具有高亲和力。 CD 36在摄取oxLDL和随后的主动脉泡沫细胞形成中起作用， 到促炎的环境。基于CD 36的致动脉粥样硬化和促炎特性，我们 假设脑中表达的CD 36作为缺血诱导的 因此，CD 36是药物干预靶点。 为了验证这些假设，目的1将研究CD 36在诱导缺血诱导的心肌细胞凋亡中的依赖性。 炎症反应和脑损伤使用两种方法：遗传学上使用CD 36敲除（KO） 小鼠和小鼠使用海沙瑞林。目的2将确定小胶质细胞/巨噬细胞CD 36 表达是缺血后炎症和脑损伤的关键介质， 在移植了以下任一种的野生型（WT）和CD 36 KO小鼠中的炎症标志物和功能结果 WT或CD 36 KO造血干细胞。小胶质细胞CD 36的作用将通过评估 在血脑屏障恶化之前的缺血后脑中的炎症反应。目标3将测试 通过在模型中检查CD 36介导的作用，确定CD 36促炎作用的临床相关性 高胆固醇血症因此，CD 36表达和配体可用性将在治疗后评估。 在易中风ApoE KO小鼠中，缺血性脑被高脂肪西方饮食喂养。此外，我们将比较 ApoE KO和ApoE/CD 36双KO小鼠中的炎症标志物和功能结局， 西方饮食以及在ApoE KO小鼠中用他汀类药物、降脂药物饲喂西方饮食。这项提议， 整体而言，将开发新的战略，重要的是改善缺血后炎症和脑 中风患者的损伤。 (lay本研究旨在探讨多功能受体CD 36是否参与了 缺血性中风后的炎症和脑损伤。了解CD 36对大脑的贡献作用 损伤将导致治疗中风患者的潜在治疗策略。

Post-ischemic inflammation complicates the development of cerebral injury triggered by ischemic stroke. CD36 is a class B scavenger receptor that has a high affinity for oxidized low-density lipoprotein (oxLDL). CD36 functions in the uptake of oxLDL and subsequent foam cell formation in aorta and may also contribute to the pro-inflammatory milieu. On the basis of proatherogenic and proinflammtory property of CD36, we hypothesize that CD36 expressed in brain functions as a primary mediator for ischemia-induced inflammation associated with cerebral injury and that CD36 is thus a target for pharmacological intervention. To test these hypotheses, Aim 1will investigate the dependency of CD36 in eliciting ischemia-induced inflammatory responses and cerebral injury using two approaches: Genetically using CD36 knock-out (KO) mice and pharmacologically using hexarelin. Aim 2 will determine whether microglia/macrophage CD36 expression is a critical mediator for post-ischemic inflammation and cerebral injury by comparing inflammatory markers and functional outcomes in wild type (WT) and CD36 KO mice transplanted with either WT or CD36 KO hematopoietic stem cells. A role for microglia CD36 will be further studied by assessing inflammatory responses in the post-ischemic brain prior to blood brain barrier deterioration. Aim 3 will test the clinical relevance of a pro-inflammatory role of CD36 by examining the CD36-mediated effects in a model of hypercholesterolemia. Accordingly, CD36 expression and ligand availability will be assessed in the post- ischemic brain in stroke-prone ApoE KO mice fed a high fat Western diet. In addition, we will compare inflammatory markers and functional outcomes in ApoE KO and ApoE/CD36 double KO mice fed the Western diet and also in ApoE KO mice fed the Western diet with statins, lipid lowering drugs. This proposal, in its entirety, will develop novel strategies important to ameliorating post-ischemic inflammation and cerebral injury in stroke victims. (lay version)This study aims to investigate whether CD36, a multifunctional receptor, is involved in inflammation and brain injury after an ischemic stroke. Understanding contributing roles of CD36 on brain injury will lead to potential therapeutic strategies to treat stroke patients.