The role of CD36 in ischemic inflammation and injury

CD36在缺血性炎症和损伤中的作用

基本信息

批准号：
7837476
负责人：
Sunghee Cho
金额：
$ 27.18万
依托单位：
WINIFRED MASTERSON BURKE MED RES INST
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7837476
关键词：
Affinity Animals Aorta Apolipoprotein E Arterial Fatty Streak Biochemical Blood - brain barrier anatomy Brain Brain Injuries CD36 gene Cerebrum Cholesterol Chronic Clinical Coronary heart disease Data Dependence Dependency Deterioration Development Diabetes Mellitus Diet Experimental Animal Model Fatty acid glycerol esters Foam Cells Generations Genetic Hematopoietic stem cells Human Infarction Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intervention Ischemia Ischemic Stroke Knock-out Knockout Mice Lead Ligands Link Lipids Low-Density Lipoproteins Mediating Mediator of activation protein Metabolic syndrome Microglia Middle Cerebral Artery Occlusion Modeling Modification Monocyte Chemoattractant Protein-1 Mus Obesity Outcome Patients Peritoneal Macrophages Pharmaceutical Preparations Plasma Play Production Property Reactive Oxygen Species Research Personnel Risk Factors Role SR-B proteins Stroke Testing Therapeutic Translating Transplantation Wild Type Mouse Work atherogenesis atorvastatin base cell type cerivastatin chemokine clinically relevant cytokine feeding functional outcomes hexarelin hypercholesterolemia inflammatory marker inhibitor/antagonist macrophage monocyte motor deficit novel strategies oxidized low density lipoprotein programs receptor scavenger receptor treatment strategy uptake

项目摘要

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.

缺血后炎症使缺血性中风引发的脑损伤的发展复杂化。 CD36 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。 CD36 在 oxLDL 的摄取和随后主动脉中泡沫细胞的形成中发挥作用，也可能有助于到促炎环境。基于 CD36 的促动脉粥样硬化和促炎特性，我们假设大脑中表达的 CD36 作为缺血诱导的主要介质炎症与脑损伤相关，因此 CD36 是药物干预的目标。为了检验这些假设，目标 1 将研究 CD36 在引发缺血诱导的过程中的依赖性使用两种方法治疗炎症反应和脑损伤：通过基因敲除 CD36 (KO) 小鼠并在药理学上使用海沙瑞林。目标 2 将确定小胶质细胞/巨噬细胞是否 CD36 通过比较，表达是缺血后炎症和脑损伤的关键介质移植任意一种的野生型 (WT) 和 CD36 KO 小鼠的炎症标志物和功能结果 WT 或 CD36 KO 造血干细胞。将通过评估进一步研究小胶质细胞 CD36 的作用血脑屏障恶化之前缺血后大脑中的炎症反应。目标 3 将进行测试通过检查模型中 CD36 介导的效应来研究 CD36 促炎作用的临床相关性高胆固醇血症。因此，CD36 表达和配体可用性将在后期进行评估。喂养高脂肪西方饮食的易中风 ApoE KO 小鼠的大脑缺血。另外，我们还会比较一下喂养 ApoE KO 和 ApoE/CD36 双 KO 小鼠的炎症标志物和功能结果西方饮食以及 ApoE KO 小鼠也用西方饮食喂养他汀类药物和降脂药物。这个提议，总的来说，将开发对改善缺血后炎症和脑损伤很重要的新策略中风患者受伤。 (外行版)本研究旨在探讨多功能受体CD36是否参与缺血性中风后的炎症和脑损伤。了解 CD36 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。