ApoE receptor-2 in vascular disease progression and regression

ApoE 受体 2 在血管疾病进展和消退中的作用

基本信息

批准号：
9889159
负责人：
David Yiu-Kwan Hui
金额：
$ 70.23万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889159
关键词：
Acute myocardial infarction Affect Alternative Splicing Amino Acids Anaphase Arginine Arterial Fatty Streak Atherosclerosis Bone Marrow Transplantation Cardiovascular Diseases Catalytic Domain Cell Aging Cell Cycle Arrest Cell Surface Receptors Cell division Cell physiology Cells Cholesterol ClinVar Clinical Code Cytokinesis Cytoplasmic Tail Data Databases Dendritic Cells Development Disease Progression Disease regression Emigrations Endothelium Etiology Event Exclusion Exons Focal Adhesions Functional disorder Gene Frequency Gene Mutation General Population Generations Genes Genetic Polymorphism Goals Human ITGAX gene Impairment In Vitro Individual Injury Intervention Knock-in Knockout Mice LDL-Receptor Related Protein 1 Lesion Ligand Binding Mediating Metaphase Mitosis Mitotic Molecular Mus Mutant Strains Mice Mutation Myeloid Cells Necrosis Patients Phosphorylation Plasma Population Prevention Process Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Proteolysis RNA Splicing Recycling Reporting Risk Risk Factors Rupture Signal Transduction Site Smooth Muscle Smooth Muscle Myocytes Suggestion Tertiary Protein Structure Testing Tissues Variant Vascular Diseases Vascular Smooth Muscle Work anaphase-promoting complex apolipoprotein E receptor 2 base cardiovascular disorder risk cardiovascular health case control cell motility combat compare effectiveness design experimental study follow-up genome wide association study genomic locus improved migration neointima formation novel personalized medicine personalized therapeutic premature premature atherosclerosis public health relevance receptor binding senescence transcriptome treatment strategy vasodilator-stimulated phosphoprotein

项目摘要

The apoE receptor-2 (apoER2) encoding gene LRP8 is a major gene locus for premature atherosclerosis and acute myocardial infarction. One apoER2 variant with the R952Q mutation (allele frequency 0.29) is associated with a 2-4 fold increase risk of acute myocardial infarction. The relationship between LRP8 polymorphism and cardiovascular disease risk is independent of plasma cholesterol levels, but the etiology associating apoER2 dysfunction with cardiovascular disease is unknown. The premise of this application is that apoER2 dysfunctions impair smooth muscle and dendritic cell functions to adversely influence atherosclerosis progression and regression. We have shown previously that apoER2 deficiency in hyperlipidemic Ldlr-/- mice accelerates atherosclerotic lesion necrosis. ApoER2 deficiency also promotes formation of cell-poor but fibrotic-rich neointima after endothelial denudation, suggestive of excessive senescence-associated secretory smooth muscle cells. Additional in vitro data revealed that apoER2 interacts with the catalytic subunit of protein phosphatase 2 (PP2A-C) in smooth muscle cells, and its absence impairs PP2A-C functions during metaphase- anaphase transition, thereby causing cell cycle arrest, mitotic slippage, and premature cell senescence. Additional preliminary studies also found apoER2 expression in CD11c+ dendritic cells and its deficiency leads to persistent phosphorylation of the focal adhesion protein VASP and the impairment of migration and efferocytosis. One goal of this project is to establish a mechanistic framework of how the cell surface receptor apoER2 modulates these intracellular events in smooth muscle cells and dendritic cells. Another goal is to test the hypothesis that apoER2 dysfunction in CD11c+ dendritic cells impedes lesion regression and works synergistically with apoER2-deficient smooth muscle cells to accelerate lesion necrosis. Mechanistic studies proposed in Aim 1 will interrogate whether cell surface receptor binding/recycling and signaling is sufficient or if generation of an apoER2 intracellular cytoplasmic domain (ICD) peptide is required for efficient smooth muscle cell cytokinesis and dendritic cell efferocytosis and migration. Aim 2 will compare the influence of apoER2 cytoplasmic splice variants and how the R952Q mutation impact on apoER2 protection against fibrotic neointimal formation after endothelial denudation and advanced atherosclerotic lesion development in hyperlipidemic Ldlr-/- mice. Aim 3 will use tissue-specific Lrp8 knockout mice as well as bone marrow transplant approach to test the hypothesis that apoER2 dysfunction in CD11c+ dendritic cells reduces the capacity for atherosclerosis lesion regression and act synergistically with smooth muscle apoER2 deficiency to accelerate atherosclerotic lesion necrosis. These studies will offer novel mechanisms depicting how the cell surface receptor apoER2 modulates intracellular events associated with cell division and motility to impact cardiovascular disease. The information may also be leveraged to design personalized therapeutic strategy to combat cardiovascular disease in a large number of individuals with Lrp8 gene polymorphism and mutation.

编码基因LRP8的APOE受体-2（ApoER2）是过早动脉粥样硬化和急性心肌梗塞。一个具有R952Q突变（等位基因频率0.29）的ApoER2变体是相关的随着2-4倍，急性心肌梗塞的风险增加。 LRP8多态性与心血管疾病风险与血浆胆固醇水平无关，但是病因与apoer2相关心血管疾病的功能障碍尚不清楚。该应用程序的前提是apoer2功能障碍损害平滑肌和树突状细胞功能，从而不利地影响动脉粥样硬化的进展和回归。我们先前已经证明了高脂血症LDLR - / - 小鼠的apoer2缺乏会加速动脉粥样硬化病变坏死。 apoer2缺乏症还促进了细胞贫困的形成，但纤维化丰富内皮剥落后的新内膜，暗示与衰老相关的分泌过度平滑肌肉细胞。其他体外数据表明，apoer2与蛋白质的催化亚基相互作用平滑肌细胞中的磷酸酶2（PP2A-C），其缺失会损害中期 - 后期过渡，从而导致细胞周期停滞，有丝分裂滑移和过早细胞衰老。其他初步研究还发现CD11C+树突状细胞中的ApoER2表达及其缺乏率。持续磷酸化的局灶性粘附蛋白VASP以及迁移损害和胞吞作用。该项目的一个目标是建立一个机械框架，以了解细胞表面受体 ApoER2在平滑肌细胞和树突状细胞中调节这些细胞内事件。另一个目标是测试 CD11C+树突状细胞中apoer2功能障碍的假设阻碍了病变的回归并起作用与ApoER2缺陷的平滑肌细胞协同加速病变坏死。机械研究在AIM 1中提出的将询问细胞表面受体结合/回收和信号是否足够或是否足够有效的平滑肌需要生成apoer2的细胞内细胞质结构域（ICD）肽细胞细胞因子和树突状细胞效应和迁移。 AIM 2将比较Apoer2的影响细胞质剪接变体以及R952Q突变如何影响apoER2防止纤维化新膜片内皮剥落和高脂症状的高级动脉粥样硬化病变后形成 LDLR - / - 小鼠。 AIM 3将使用组织特异性LRP8敲除小鼠以及骨髓移植方法测试CD11C+树突状细胞中ApoER2功能障碍的假设降低了动脉粥样硬化的能力病变回归并与平滑肌apoer2缺乏症协同作用，以加速动脉粥样硬化病变坏死。这些研究将提供新的机制，描绘了细胞表面受体apoer2 调节与细胞分裂相关的细胞内事件以及影响心血管疾病的运动。这信息也可能被利用来设计个性化的治疗策略来对抗心血管疾病在大量患有LRP8基因多态性和突变的个体中。