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。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在主动脉中的oxLDL摄取和随后的泡沫细胞形成中起作用，并且也可能有助于促炎环境。基于CD 36的致动脉粥样硬化和促炎症特性，我们假设脑中表达的CD 36作为与脑损伤相关的缺血诱导的炎症的主要介质发挥作用，因此CD 36是药物干预的靶点。为了检验这些假设，目的1将使用两种方法研究CD 36在引发缺血诱导的炎症反应和脑损伤中的依赖性：使用CD 36敲除（KO）小鼠的遗传学方法和使用海沙瑞林的免疫学方法。目的2将通过比较移植有WT或CD 36 KO造血干细胞的野生型（WT）和CD 36 KO小鼠的炎症标志物和功能结果，确定小胶质细胞/巨噬细胞CD 36表达是否是缺血后炎症和脑损伤的关键介质。小胶质细胞CD 36的作用将通过评估血脑屏障恶化前缺血后脑中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查CD 36介导的作用来测试CD 36的促炎作用的临床相关性。因此，将在喂食高脂肪西方饮食的易卒中ApoE KO小鼠的缺血后脑中评估CD 36表达和配体可用性。此外，我们将比较喂食西方饮食的ApoE KO和ApoE/CD 36双KO小鼠以及喂食西方饮食和他汀类降脂药物的ApoE KO小鼠的炎症标志物和功能结局。这项建议，在其整体上，将开发新的战略，重要的是改善缺血后炎症和脑损伤的中风受害者。 本研究旨在探讨CD 36作为一种多功能受体是否参与缺血性卒中后的炎症和脑损伤。了解CD 36在脑损伤中的作用将为治疗中风患者提供潜在的治疗策略。(End摘要）

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)