Efflux proteins and insulin resistance in atherogenesis

动脉粥样硬化中的外流蛋白和胰岛素抵抗

• 批准号: 7406106
• 负责人: DAVID P HAJJAR
• 金额: $ 64.97万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406106
• 关键词: Adhesions; Animal Model; Animals; Antiatherogenic; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Bone Marrow; Bone Marrow Transplantation; CD36 gene; Cholesterol; Condition; Data; Development; Diet; Disease; Excision; Family; Fatty acid glycerol esters; Foam Cells; Glucose; Glycoproteins; Goals; Hand; Health; Hematopoietic stem cells; Homeostasis; Human; Hyperlipidemia; Insulin Resistance; Knockout Mice; Lesion; Ligands; Lipids; Lipoproteins; Low-Density Lipoproteins; Maintenance; Mediator of activation protein; Modeling; Mus; Pathway interactions; Pattern; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physiological; Process; Property; Proteins; Regulation; Resistance; Risk Factors; Role; Signaling Molecule; Stem cells; Tissues; Transplantation; Treatment Protocols; Work; atherogenesis; atheroprotective; base; cytokine; design; fatty acid metabolism; fatty acid transport; homologous recombination; in vivo; insulin sensitivity; lipid transport; macrophage; receptor function; research study; scavenger receptor; transcription factor

CD36 is a broadly expressed 88 kD transmembrane glycoprotein which functions as a scavenger receptor, adhesion and signaling molecule and a facilitator of fatty acid transport. Previous work by our group and others determined that CD36 was a major mediator of macrophage foam cell formation and atherogenesis. Recently, a paradox has emerged: significant protection against lesion development and progression was observed in experimental conditions where CD36 was rendered absent genetically and when CD36 was upregulated by pharmacological means. Using stem cell transfer of CD36/apoE bone marrow into apoE null animals, we found that the atheroprotective effect afforded by complete absence of CD36 was not fully realized. Thus, a major hypothesis of this application is that CD36 has atheroprotective properties independent of its role as a scavenger receptor. Based on emerging data, we focus on the role of CD36 in efflux pathways and in modulating insulin-resistance, both of which are stimulated by drugs which activate PPARs, transcription factors which regulate CD36 expression. We hypothesize that CD36 is a critical player in maintenance of vessel wall homeostasis, and that entry of cholesterol into macrophages via CD36 facilitates removal of pro-atherogenic modified LDL from the intima, and ultimately allows lipid clearance through efflux pathways. Elucidation of the regulation of CD36 in relationship to the major efflux pathways is a major goal of our studies. Insulin resistance is a separate risk factor for atherogenesis and results in its premature development. We hypothesize that a portion of the protective role of CD36 in atherogenesis is related to its effect on glucose and fatty acid metabolism. We will utilize unique animal models we have on hand to explore the differential impact of CD36 on atherosclerosis based on scavenger receptor function or its role as a facilitator of fatty acid transport and determinant of insulin sensitivity. These approaches will enable us to design more specific treatment regimens which will ultimately impact on human health and disease.

CD 36是一种广泛表达的88 kD跨膜糖蛋白，具有清道夫受体、粘附分子、信号分子和脂肪酸转运促进剂的功能。我们小组和其他人以前的工作确定了CD 36是巨噬细胞泡沫细胞形成和动脉粥样硬化形成的主要介质。最近，出现了一个悖论：显着的保护病变的发展和进展，观察到在实验条件下，CD 36是呈现遗传缺乏和当CD 36被上调的药理学手段。用干细胞将CD 36/apoE骨髓移植到apoE缺失的骨髓中 在动物中，我们发现完全缺乏CD 36所提供的动脉粥样硬化保护作用没有完全实现。因此，本申请的一个主要假设是CD 36具有与其作为清道夫受体的作用无关的动脉粥样硬化保护特性。基于新出现的数据，我们专注于CD 36在外排途径和调节胰岛素抵抗中的作用，这两者都是由激活PPARs的药物刺激的，PPARs是调节CD 36表达的转录因子。我们假设CD 36是维持血管壁稳态的关键因素，胆固醇通过CD 36进入巨噬细胞有助于从内膜中清除促动脉粥样硬化修饰的LDL，并最终通过外排途径清除脂质。阐明与主要外排途径相关的CD 36调节 是我们研究的主要目标。胰岛素抵抗是动脉粥样硬化形成的独立危险因素，并导致其过早发展。我们推测CD 36在动脉粥样硬化形成中的保护作用部分与其对葡萄糖和脂肪酸代谢的影响有关。我们将利用我们手头上独特的动物模型，探索基于清道夫受体功能或其作为脂肪酸转运促进剂和胰岛素敏感性决定因素的作用，CD 36对动脉粥样硬化的不同影响。这些方法将使我们能够设计更具体的治疗方案，最终影响人类健康和疾病。