Defective isoforms of ApoE induce atherogenesis via unfolded protein responses

描述（由申请人提供）：本项目研究载脂蛋白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，使用部分卷曲肽（R5-6C）作为激活这些受体的工具。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。我们最近报道了apoER2和VLDLR在小鼠巨噬细胞中被它们的天然配体apoE和reelin激活，导致禁用-1 （Dab1）的激活，atp结合盒转运体A1 （ABCA1）表达上调，加速胆固醇外排和减少细胞胆固醇积累。然而，其他一些研究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或抗动脉粥样硬化作用，可能依赖于特定的配体和所涉及的信号通路。具体来说，抗动脉粥样硬化配体，如reelin、apoE和活化蛋白C (APC)，激活dab1依赖的信号通路，抑制可能导致炎症和泡沫细胞形成的细胞事件。在

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.