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。 CD36是一种B类清道夫受体，与氧化型低密度脂蛋白(OxLDL)有很高的亲和力。 CD36在主动脉摄取oxLDL和随后的泡沫细胞形成中起作用，也可能参与 去支持发炎的环境。基于CD36的致动脉粥样硬化和促炎作用，我们 脑内CD36的表达可能是脑缺血的主要调节因子 与脑损伤相关的炎症，因此CD36是药物干预的靶点。 为了验证这些假说，目标1将调查CD36在诱导缺血诱导中的依赖性 使用两种方法的炎症反应和脑损伤：从基因上使用CD36基因敲除(KO) 小鼠和使用六氢瑞林的药理作用。目标2将确定小胶质细胞/巨噬细胞CD36 表达是脑缺血后炎症和脑损伤的关键介质 野生型(WT)和CD36 KO小鼠移植的炎症标志物和功能结局 WT或CD36KO造血干细胞。小胶质细胞CD36的作用将通过评估进一步研究 血脑屏障恶化前脑缺血后的炎症反应。AIM 3将测试 通过检测CD36介导的模型效应来研究CD36的促炎作用的临床意义 高胆固醇血症。因此，CD36的表达和配体的可用性将在术后进行评估 易中风的ApoE KO小鼠的脑缺血，喂食高脂肪的西方饮食。此外，我们还将比较 ApoE KO和ApoE/CD36双重KO小鼠的炎症标志物和功能结局 在西方饮食和在ApoE KO小鼠中喂以他汀类药物的西方饮食，降脂药物。这项提议， 作为整体，将开发新的策略，对改善缺血后炎症和脑 中风患者的受伤情况。 (通俗版)本研究旨在调查多功能受体CD36是否参与了 缺血性中风后的炎症和脑损伤。了解CD36在脑中的作用 损伤将导致潜在的治疗策略来治疗中风患者。

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.