Unraveling ApoE4 Promotion of Cardiometabolic Disease

揭示 ApoE4 对心血管代谢疾病的促进作用

• 批准号: 10283188
• 负责人: PHILIP W SHAUL
• 金额: $ 34.87万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283188
• 关键词: Administrative Supplement; Adverse effects; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Apolipoprotein E; Attenuated; Blood Vessels; Blood coagulation; Brain; Cardiometabolic Disease; Cell Line; Cellular biology; Endothelial Cells; Endothelium; Future; Genetic; Impairment; Individual; Insulin; Insulin Resistance; Intervention; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Liver; Mediating; Mus; Muscle; Parents; Pathologic; Peripheral; Process; Research; Risk; Skeletal Muscle; Testing; Thrombosis; Work; apolipoprotein E receptor 2; apolipoprotein E-3; apolipoprotein E-4; base; cognitive function; genetic risk factor; genetic variant; insight; mouse model; negative affect; prevent; programs

Project Summary/Abstract The greatest genetic risk factor for late-onset Alzheimer’s disease (AD) is the ε4 allele of apolipoprotein E (apoE), or apoE4. In work in our parent R01 project entitled “Unraveling ApoE4 Promotion of Cardiometabolic Disease” we have discovered in mice that apoE4 actions via the apoE receptor apoER2 in endothelial cells attenuate endothelial insulin transport to the skeletal muscle to cause peripheral insulin resistance. We have also discovered that apoE4 is prothrombotic, most likely also through processes mediated by endothelial apoER2. We are in the process of testing if genetic correction of apoE4 to apoE3 in the liver by base editing reverses the negative impact of apoE4 on peripheral insulin resistance and thrombosis. The newly-discovered adverse effects of apoE4 on endothelial insulin transport and thrombosis may be critically involved in the detrimental impact of apoE4 on AD. Therefore, in the administrative supplement project we propose to determine if via endothelial apoER2, apoE4 impairs CNS insulin delivery and action and promotes CNS microvascular thrombosis. We also propose to determine if base editing of apoE4 to apoE3 in the liver prevents the adverse effects of apoE4 in the CNS. Doing so will determine how liver-derived apoE4 impacts processes in the CNS, and also provide a potential means to prevent adverse processes in the CNS caused by apoE4 without requiring intervention within the CNS. Positive results in the administrative supplement project will lead to a new and unique future R01 project in which we determine in a mouse model of AD how the revealed mechanisms contribute to the adverse impact of apoE4 on AD pathologic features and AD-related impairment in cognitive function. In the future project we will additionally determine if base editing of apoE4 to apoE3 in the liver reverses the detrimental effects of apoE4 on AD. Thus, springboarding from recent discoveries in our parent R01 project, the administrative supplement project will allow us to leverage our expertise in endothelial cell biology to gain new insights about apoE4 actions relevant to AD and possible means to negate them.

项目概要/摘要 晚发性阿尔茨海默病 (AD) 的最大遗传风险因素是载脂蛋白的 ε4 等位基因 E (apoE)，或 apoE4，正在我们的母 R01 项目中工作，题为“解开 ApoE4 对心脏代谢的促进作用”。 我们在小鼠体内发现，apoE4 通过内皮细胞中的 apoE 受体 apoER2 发挥作用 减弱内皮胰岛素向骨骼肌的转运，导致外周胰岛素抵抗。 还发现 apoE4 具有促血栓形成作用，很可能也是通过内皮细胞介导的过程 我们正在测试是否通过碱基编辑将肝脏中的 apoE4 基因校正为 apoE3。 逆转 apoE4 对外周胰岛素抵抗和血栓形成的负面影响。 apoE4 对内皮胰岛素转运和血栓形成的不利影响可能与 apoE4对AD的不良影响因此，在行政补充项目中我们建议确定。 如果通过内皮 apoER2、apoE4 损害 CNS 胰岛素输送和作用并促进 CNS 微血管 我们还建议确定肝脏中 apoE4 碱基编辑是否可以预防不良反应。 apoE4 在中枢神经系统中的作用将确定肝源性 apoE4 如何影响中枢神经系统的过程， 还提供了一种潜在的方法来预防由 apoE4 引起的中枢神经系统不良过程，而无需 行政补充项目的积极成果将带来新的和新的结果。 独特的未来 R01 项目，我们在 AD 小鼠模型中确定如何揭示机制 导致 apoE4 对 AD 病理特征和 AD 相关认知障碍的不利影响 在未来的项目中，我们还将确定肝脏中 apoE4 到 apoE3 的碱基编辑是否会逆转。 apoE4 对 AD 的影响 因此，从我们母公司 R01 项目的最新发现出发， 行政补充项目将使我们能够利用我们在内皮细胞生物学方面的专业知识来获得 关于与 AD 相关的 apoE4 作用的新见解以及消除它们的可能方法。