Defective isoforms of ApoE induce atherogenesis via unfolded protein responses

ApoE 的缺陷异构体通过未折叠的蛋白质反应诱导动脉粥样硬化形成

基本信息

批准号：
9223726
负责人：
HONG YANG
金额：
$ 36.38万
依托单位：
MEHARRY MEDICAL COLLEGE
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：
2009-09-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223726
关键词：
ATP-Binding Cassette Transporters Adenovirus Vector Adhesions Agonist Antiatherogenic Antiphospholipid Antibodies Aorta Apolipoprotein E Apolipoproteins B Area Arterial Fatty Streak Atherosclerosis Binding C-terminal Cell Adhesion Cell Adhesion Molecules Characteristics Cholesterol Cholesterol Esters Cholesterol Homeostasis Coronary heart disease Data Development Disabled Persons Disease Endothelial Cells Esterification Event Extracellular Matrix Proteins Factor XI Family Foam Cells Gene Expression Gene Transfer Genes Glucose Histologic Hydrolysis In Vitro Inflammation Injectable Knockout Mice LDL-Receptor Related Protein 1 Lesion Ligands Lipids Lipoprotein Binding Lipoproteins Low Density Lipoprotein Receptor MAPK14 gene Mediating Mus N Domain N-terminal Oxides Pathogenesis Pathway interactions Peptides Plasma Prevention strategy Protein Isoforms Proteins Receptor Activation Recombinants Reporting Research Research Personnel Role Signal Pathway Signaling Protein Smooth Muscle Myocytes Stroke Tandem Repeat Sequences Testing Therapeutic Transgenes Up-Regulation VLDL receptor Very low density lipoprotein activated Protein C apolipoprotein E receptor 2 atherogenesis atheroprotective design experimental study human neutrophil peptide 4 in vivo interest macrophage mimetics monocyte mouse model neutrophil novel strategies protective effect public health relevance receptor receptor binding response tool uptake

项目摘要

DESCRIPTION (provided by applicant): This project investigates the anti-atherogenic role of apolipoprotein E receptor 2 (apoER2) and very low- density lipoprotein receptor (VLDLR), using a partial reelin peptide (R5-6C) as a tool to activate these receptors. These studies extend our research on the pathogenesis of, and therapeutic strategies for atherosclerosis. We recently reported that activation of apoER2 and VLDLR by their natural ligands apoE and reelin in murine macrophages results in activation of disabled-1 (Dab1), upregulation of ATP-binding cassette transporter A1 (ABCA1) expression, accelerated cholesterol efflux and reduced cellular cholesterol accumulation. However a number of other investigators studying the impact of VLDLR and apoER2 on the pathogenesis of atherosclerosis noted that activation of these receptors is able to induce either pro- or anti- atherogenic effects, possibly dependent on the particular ligands and signaling pathways involved. Specifically, anti-atherogenic ligands, such as reelin, apoE and activated protein C (APC), activate a Dab1-dependent signaling pathway and inhibit cellular events that potentially contribute to inflammation and foam cell formation. In contrast pro-atherogenic ligands such as lipoproteins, neutrophil peptides and coagulation factor XI, elevate intracellular cholesterol accumulation and induce cell adhesion, possibly by activation of a p38-mediated pathway. This project is designed to define the anti-atherogenic role of VLDLR/apoER2 in vitro and in vivo, using a partial reelin peptide (R5-6C) as an agonist. We chose reelin because it exclusively binds VLDLR and apoER2. In contrast, apoE and APC are able to interact with other receptors as well as VLDLR and apoER2. Our central hypothesis is that activation of the VLDLR/apoER2-Dab1 pathway by R5-6C will upregulate anti- atherogenic molecules, down-regulate pro-atherogenic molecules, and therefore inhibit atherosclerosis development. SA1 will study the effect of R5-6C gene transfer on atherosclerosis in mouse models. Though the primary focus is atherosclerotic lesions, we will also study the effect of R5-6C gene transfer on the expression of pro- and anti-atherogenic proteins in the atherosclerotic area as well as on the level of plasma lipids/glucose. SA2 will tes a working hypothesis that R5-6C inhibits oxLP-induced adhesion of monocytes (MNCs) to endothelial cells (ECs) by activation of the apoER2/VLDLR-Dab1 pathway. An emphasis will be placed on the contribution of VLDLR/apoER2-Dab1 pathway to R5-6C-induced changes in adhesion of MNCs to ECs and the expression of endothelial anti- and pro-adhesion molecules. SA3 will test a working hypothesis that R5-6C inhibits foam cell formation by activation of the apoER2/VLDLR-Dab1 pathway. Experiments are designed to explore whether R5-6C blocks macrophage binding and uptake of lipoproteins, and whether activation of the VLDLR/apoER2- Dab1 pathway is a mechanism by which R5-6C regulates the expression of genes related to cholesterol metabolism and inhibits foam cell formation. If successful, this project will provide a scientific basis for designing VLDLR/apoER2 agonists, such as reelin mimetics, to treat atherosclerosis.

描述（由申请人提供）：该项目研究载脂蛋白 E 受体 2 (apoER2) 和极低密度脂蛋白受体 (VLDLR) 的抗动脉粥样硬化作用，使用部分 reelin 肽 (R5-6C) 作为激活这些受体的工具受体。这些研究扩展了我们对动脉粥样硬化发病机制和治疗策略的研究。我们最近报道，在小鼠巨噬细胞中，apoER2 和 VLDLR 的天然配体 apoE 和 reelin 激活，导致禁用-1 (Dab1) 激活、ATP 结合盒转运蛋白 A1 (ABCA1) 表达上调、加速胆固醇外流并降低细胞胆固醇积累。然而，许多其他研究 VLDLR 和 apoER2 对动脉粥样硬化发病机制影响的研究人员指出，这些受体的激活能够诱导促动脉粥样硬化或抗动脉粥样硬化作用，可能取决于所涉及的特定配体和信号传导途径。具体来说，抗动脉粥样硬化配体，例如 reelin、apoE 和活化蛋白 C (APC)，可激活 Dab1 依赖性信号通路并抑制可能导致炎症和泡沫细胞形成的细胞事件。在对比促动脉粥样硬化配体，如脂蛋白、中性粒细胞肽和凝血因子 XI，可能通过激活 p38 介导的途径，提高细胞内胆固醇积累并诱导细胞粘附。该项目旨在使用部分 reelin 肽 (R5-6C) 作为激动剂，在体外和体内确定 VLDLR/apoER2 的抗动脉粥样硬化作用。我们选择 reelin 是因为它专门结合 VLDLR 和 apoER2。相比之下，apoE 和 APC 能够与其他受体以及 VLDLR 和 apoER2 相互作用。我们的中心假设是，R5-6C 激活 VLDLR/apoER2-Dab1 途径将上调抗动脉粥样硬化分子，下调促动脉粥样硬化分子，从而抑制动脉粥样硬化的发展。 SA1将研究R5-6C基因转移对小鼠模型动脉粥样硬化的影响。虽然主要焦点是动脉粥样硬化病变，但我们还将研究 R5-6C 基因转移对动脉粥样硬化区域促动脉粥样硬化和抗动脉粥样硬化蛋白表达以及血浆脂质/葡萄糖水平的影响。 SA2 将测试一个工作假设，即 R5-6C 通过激活 apoER2/VLDLR-Dab1 途径抑制 oxLP 诱导的单核细胞 (MNC) 与内皮细胞 (EC) 的粘附。重点将放在 VLDLR/apoER2-Dab1 通路对 R5-6C 诱导的 MNC 与 EC 粘附变化以及内皮抗粘附和促粘附分子表达的贡献上。 SA3 将测试一个工作假设，即 R5-6C 通过激活 apoER2/VLDLR-Dab1 途径抑制泡沫细胞形成。实验旨在探讨R5-6C是否阻断巨噬细胞结合和脂蛋白的摄取，以及VLDLR/apoER2-Dab1通路的激活是否是R5-6C调节胆固醇代谢相关基因表达并抑制泡沫细胞形成的机制。如果成功，该项目将提供设计 VLDLR/apoER2 激动剂（例如 reelin 模拟物）治疗动脉粥样硬化的科学依据。