权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10582114
负责人：
David Yiu-Kwan Hui
金额：
$ 7.35万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10582114
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.

载脂蛋白E受体-2(ApoER2)编码基因LRP8是早发动脉粥样硬化的主要基因座。急性心肌梗塞。一个ApoER2变异与R952Q突变(等位基因频率0.29)相关患急性心肌梗塞的风险增加2-4倍。LRP8基因多态与遗传易感性的关系心血管疾病的风险与血浆胆固醇水平无关，但与ApoER2相关的病因学心血管疾病的功能障碍是未知的。这一应用的前提是ApoER2功能障碍损害平滑肌和树突状细胞的功能，对动脉粥样硬化的进展和回归。我们以前已经证明，高脂血症Ldlr-/-小鼠的ApoER2缺乏加速动脉粥样硬化性病变坏死。ApoER2缺乏也促进细胞贫乏但富含纤维化的形成内皮剥离后的新生内膜，提示过度衰老相关的分泌平滑肌肉细胞。更多的体外数据显示，ApoER2与蛋白质的催化亚单位相互作用平滑肌细胞中的磷酸酶2(PP2A-C)及其缺失会损害PP2A-C在细胞分裂中期的功能后期过渡，从而导致细胞周期停滞、有丝分裂滑移和细胞过早衰老。进一步的初步研究也发现ApoER2在CD11c+树突状细胞中的表达及其缺陷导致与粘着斑蛋白Vasp的持续磷酸化和迁移和泡泡细胞增多症。这个项目的一个目标是建立一个机制框架，研究细胞表面受体如何 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ApoER2功能障碍阻碍病变消退的假说与ApoER2缺失的平滑肌细胞协同作用，加速病变坏死。机械学研究在目标1中提出的将询问细胞表面受体结合/再循环和信号传递是否充分或高效的平滑肌需要ApoER2胞内胞浆结构域(ICD)多肽的产生细胞胞质分裂和树突状细胞吞噬和迁移。目标2将比较ApoER2的影响细胞质剪接变异体和R952Q突变如何影响ApoER2对纤维化新生内膜的保护作用高脂血症患者内皮剥脱后的形成和晚期动脉粥样硬化病变的发展 LDLR-/-小鼠。AIM 3将使用组织特异性Lrp8基因敲除小鼠以及骨髓移植方法来验证CD11c+树突状细胞ApoER2功能障碍降低动脉粥样硬化能力的假说病变消退与血管ApoER2缺乏症协同作用加速动脉粥样硬化病变坏死。这些研究将提供描述细胞表面受体ApoER2如何调节与细胞分裂和运动相关的细胞内事件，以影响心血管疾病。这个信息也可以被用来设计个性化的治疗策略来对抗心血管疾病在大量个体中携带Lrp8基因的多态和突变。