Unraveling ApoE4 Promotion of Cardiometabolic Disease

揭示 ApoE4 对心血管代谢疾病的促进作用

基本信息

批准号：
10620700
负责人：
PHILIP W SHAUL
金额：
$ 57.04万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620700
关键词：
Address Adhesions Amino Acids Aorta Apolipoprotein E Atherosclerosis Beta Cell Blood Platelets Blood Vessels Blood coagulation Cardiometabolic Disease Cardiovascular Diseases Catalytic Domain Cell Culture Techniques Cell Line Co-Immunoprecipitations Coronary Arteriosclerosis DAB2 gene Data Data Set Development Endothelial Cells Endothelium Enzyme Activation Genes Genetic Genetic Processes Goals Health Hepatocyte Human Individual Insulin Insulin Resistance Intervention LDL-Receptor Related Protein 1 Ligands Link Lipids Liver MAPK8 gene Mass Spectrum Analysis Mediating Metabolic Metabolic Diseases Mus Muscle Nitric Oxide Synthase Non-Insulin-Dependent Diabetes Mellitus Pathogenesis Population Process Protein Isoforms Protein Phosphatase 2A Regulatory Subunit PR53 Protein Subunits Protein phosphatase Proteins Research Risk SP600125 Signal Transduction Skeletal Muscle Testing Thrombosis Validation Vascular Diseases Venous Thrombosis Work apolipoprotein E receptor 2 apolipoprotein E-3 apolipoprotein E-4 base editing base editor blood glucose regulation cardiometabolism cardiovascular disorder risk cohort genetic variant genome wide association study in vivo inhibitor lipid transport monocyte novel therapeutics pre-clinical preservation prevent programs recruit scaffold von Willebrand Factor

项目摘要

Project Summary/Abstract Compared with individuals expressing the most common genetic variant of apolipoprotein E (apoE), apoE3, those harboring apoE4 are at increased risk of both cardiovascular disease and type 2 diabetes mellitus (T2DM). Although apoE classically participates in lipid transport, the basis for apoE4-associated risk remains unclear, and there are no interventions available to break the link between apoE4 and vascular and metabolic disorders. We recently discovered that the insulin resistance observed in mice expressing human apoE4 is driven by skeletal muscle insulin resistance mediated by the apoE receptor apoER2 in endothelial cells. Studies in culture showed that the underlying mechanism is apoE4-apoER2-induced inhibition of endothelial cell insulin transport, which has a major impact on insulin action in muscle. In other recent work we determined that thrombosis is markedly more severe in apoE4- versus apoE3-expressing mice. Cell culture studies further indicated that this may be due to apoE4 promotion of von Willebrand factor (vWF) secretion by endothelial cells. The Overall Goal of the proposed research is to elucidate how apoE4 actions on endothelium influence glucose homeostasis and vascular disease pathogenesis. Aim 1 will determine how apoE4 causes insulin resistance. A non-biased query of apoER2-interacting proteins and ensuing studies of insulin transport in cultured endothelial cells suggest involvement of Dab2-interacting protein (DAB2IP) and JIP1, which both modulate JNK signaling. Using endothelial cell-specific deletion in apoE3- and apoE4- expressing mice, we will test the hypothesis that apoE4 promotes insulin resistance via endothelial apoER2 through DAB2IP- and JIP1-dependent mechanisms. Aim 2 will determine how apoE4 promotes atherosclerosis and thrombosis. Studies of proteins interacting with apoER2 in endothelium and apoE4 enhancement of endothelial cell vWF secretion and monocyte adhesion indicate possible participation of the protein phosphatase PP2A. In apoE3- and apoE4-expressing mice we will test the hypothesis that apoE4 promotes atherosclerosis and thrombosis via endothelial apoER2-related activation of PP2A. In Aims 1 and 2, we will additionally use GWAS-based strategies to determine if the operative genes in mice are modifier genes influencing apoE4-related risk of metabolic and vascular disease in humans. In Aim 3 we will devise interventions against apoE4 and its mechanisms of action to preserve metabolic and vascular health. In apoE4 mice the effect of JNK inhibition on insulin resistance and the effect of PP2A inhibition on atherosclerosis and thrombosis will be evaluated. We will also use base editing to genetically correct apoE4 to apoE3 in vivo in the hepatocytes of apoE4 mice. Editing efficiency and impact on apoE4-related insulin resistance, atherosclerosis and thrombosis will be evaluated. By accomplishing these Aims and unraveling how apoE4 promotes cardiometabolic disease, it is expected that novel therapies can then be developed to neutralize an important genetic contribution to metabolic and vascular disease in 15 to 20% of the population.

项目摘要/摘要与表达载脂蛋白E（APOE）最常见遗传变异的个体相比 APOE3，携带APOE4的人患心血管疾病和2型糖尿病的风险增加 Mellitus（T2DM）。尽管ApoE经典地参与脂质运输，但与APOE4相关风险的基础尚不清楚，并且没有任何干预措施可以打破ApoE4和血管之间的联系代谢障碍。我们最近发现，在表达人的小鼠中观察到的胰岛素抗性 APOE4由apoE受体ApoER2在内皮中介导的骨骼肌胰岛素抵抗驱动细胞。培养研究表明，潜在机制是APOE4-APOER2诱导的抑制内皮细胞胰岛素转运，对肌肉中的胰岛素作用产生重大影响。在最近的其他工作中我们确定在APOE4中与表达APOE3的小鼠的血栓形成明显更为严重。细胞培养研究进一步表明，这可能是由于APOE4促进了Von Willebrand因子（VWF）内皮细胞的分泌。拟议的研究的总体目标是阐明APOE4如何行动在内皮上影响葡萄糖稳态和血管疾病发病机理。 AIM 1将决定如何 APOE4引起胰岛素抵抗。 apoer2相互作用蛋白的无偏见查询，然后研究培养的内皮细胞中的胰岛素转运表明DAB2相互作用蛋白（DAB2IP）和 JIP1，都调节JNK信号传导。在APOE3和APOE4-中使用内皮细胞特异性缺失 - 表达小鼠，我们将测试APOE4通过内皮apoer2促进胰岛素抵抗的假设2 通过DAB2IP和JIP1依赖性机制。 AIM 2将决定APOE4如何促进动脉粥样硬化和血栓形成。研究与内皮和APOE4中ApoER2相互作用的蛋白质的研究内皮细胞VWF分泌和单核细胞粘附的增强表明可能参与蛋白质磷酸酶PP2A。在表达APOE3和APOE4的小鼠中，我们将测试APOE4的假设通过内皮apoer2相关的PP2A激活促进动脉粥样硬化和血栓形成。在目标1和2中我们还将使用基于GWAS的策略来确定小鼠的手术基因是否为修饰符影响人类代谢和血管疾病的APOE4相关风险的基因。在AIM 3中，我们将设计针对APOE4的干预措施及其保护代谢和血管健康的作用机制。在 APOE4小鼠JNK抑制对胰岛素抵抗的影响以及PP2A抑制对将评估动脉粥样硬化和血栓形成。我们还将使用基础编辑来遗传纠正APOE4 在apoE4小鼠的肝细胞中的apoe3 in act in apoE3。编辑效率和对APOE4相关胰岛素的影响将评估耐药性，动脉粥样硬化和血栓形成。通过实现这些目标并解开 APOE4如何促进心脏代谢疾病，可以预期，新型疗法可以开发为中和15％至20％的人口中对代谢和血管疾病的重要遗传贡献。