The role of CD36 in ischemic inflammation and injury

描述(由申请人提供)： 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在摄取oxLDL和随后的主动脉泡沫细胞形成中起作用，也可能有助于促炎环境的形成。根据CD36的促动脉粥样硬化和促炎作用，我们推测CD36在脑内的表达是脑损伤相关的缺血性炎症反应的主要介质，因此CD36是药物干预的靶点。为了验证这些假设，目标1将使用两种方法来研究CD36在引发缺血诱导的炎症反应和脑损伤中的依赖性：通过遗传方法使用CD36基因敲除(KO)小鼠和使用六氢瑞林进行药理学研究。目的2通过比较野生型(WT)和CD36KO小鼠移植WT和CD36KO造血干细胞后的炎症标志物和功能结果，确定小胶质细胞/巨噬细胞CD36的表达是否是脑缺血后炎症和脑损伤的关键介质。小胶质细胞CD36的作用将通过在血脑屏障恶化之前评估缺血后脑内的炎症反应来进一步研究。目的3将通过在高胆固醇血症模型中检测CD36介导的作用来测试CD36的促炎作用的临床相关性。因此，CD36的表达和配体的可用性将在易中风的ApoE KO小鼠的脑缺血后进行评估，这些小鼠喂养高脂肪的西方饮食。此外，我们还将比较喂食西方饮食的ApoE KO和ApoE/CD36双重KO小鼠以及喂食降脂药物他汀类药物的ApoE KO小鼠的炎症标志物和功能结果。这项提议的全部内容将开发新的策略，对改善中风患者的缺血后炎症和脑损伤非常重要。 本研究旨在探讨多功能受体CD36是否参与了缺血性卒中后的炎症和脑损伤。了解CD36在脑损伤中的作用将导致潜在的治疗策略来治疗中风患者。(摘要结束)

DESCRIPTION (provided by applicant): 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 proinflammatory 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 1 will 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. 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. (End of Abstract)