Polymorphic ApoE at the crossroad of lipid metabolism and inflammation in atherosclerosis

多态性 ApoE 处于动脉粥样硬化脂质代谢和炎症十字路口

基本信息

批准号：
10533337
负责人：
David Yiu-Kwan Hui
金额：
$ 61.49万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10533337
关键词：
Acceleration Adipocytes Adipose tissue Adrenal Glands Agonist Alleles Alzheimer&apos s Disease Apolipoprotein E Area Arterial Fatty Streak Atherosclerosis Biomedical Research Blood Vessels Bone Marrow Cells Bone Marrow Transplantation Brain CETP gene Cardiovascular Diseases Carotid Arteries Carotid Atherosclerotic Disease Cause of Death Cell Death Cells Cholesterol Coronary Coronary Arteriosclerosis Data Diabetes Mellitus Diet Disease E protein Experimental Animal Model Extrahepatic Follow-Up Studies Functional disorder Genes Genetic Polymorphism Genetic study Genotype Goals Hepatic Hepatic Tissue Hepatocyte Heterozygote Homeostasis Human Hyperlipoproteinemia Type III Immune Impairment Inflammasome Inflammation Inflammatory Inflammatory Response Intervention Knock-out Lesion Lipids Lipoproteins Liver Macrophage Metabolic dysfunction Metabolic stress Mus Mutation Myelogenous Myeloid Cells Myelopoiesis Necrosis Obesity Oxidative Stress Oxidative Stress Induction Pathogenesis Peripheral Vascular Diseases Phase Plasma Population Population Study Property Risk Risk Factors Role Severities Signal Transduction Smooth Muscle Smooth Muscle Myocytes Testing Time Tissues Transplantation Triglycerides Tunica Adventitia Variant Vascular Diseases apolipoprotein E-3 apolipoprotein E-4 atherogenesis cardiovascular disorder risk cardiovascular risk factor cell type cytokine design effectiveness testing endoplasmic reticulum stress gene replacement genetic risk factor improved lipid metabolism non-diabetic novel novel therapeutic intervention overexpression personalized intervention public health relevance recruit single nucleus RNA-sequencing single-cell RNA sequencing sphingomyelin synthase western diet

项目摘要

ABSTRACT Additional novel therapeutic strategies based on better understanding of how specific genetic risk factors participate in the pathogenesis and pathophysiology of cardiovascular disease are necessary to further reduce the burden associated with this major cause of death. A major genetic risk factor of cardiovascular disease is polymorphisms in the APOE gene. ApoE is synthesized in many cell types and the importance of liver-derived apoE in maintaining plasma lipid homeostasis is well documented. How does apoE (dys)function in other cell type influences atherosclerosis has not been delineated completely. The goal of this project is to ascertain how each apoE variant expressed in myeloid cells and adipocytes influences atherosclerosis. Preliminary results showed that: (i) bone marrow cells from human APOE2 and APOE4 gene replacement mice were less effective than APOE3 cells to reduce atherosclerosis in ApoE-/- mice; (ii) apoE2 and apoE4 enhance myeloid cell inflammatory response via distinct mechanisms; and (iii) APOE2 but not APOE3 or APOE4 adipocytes are dysfunctional with elevated intracellular cholesterol content to accelerate inflammation and atherogenesis. Our premise is that apoE2 and apoE4 augment inflammation and metabolic dysfunctions through distinct mechanisms, and in a cell type-specific manner, to accelerate atherosclerosis. Our hypothesis is that apoE2 causes cellular dysfunction through impaired intracellular cholesterol efflux, whereas apoE4 causes myeloid cell dysfunction by inducing oxidative and ER stress. Aim 1 will test the hypothesis that myeloid apoE2 expression increases myelopoiesis and promote early stages of atherogenesis, whereas myeloid apoE4 accelerates atherosclerosis advancement to later stages due to its impairment of efferocytosis and metabolic stress. Single- cell RNA-seq will be performed on lesion smooth muscle and immune cells at 3 stages of atherosclerosis to delineate how each apoE variant expressed in myeloid cells influences smooth muscle cell plasticity and lesion immune cell repertoire to alter lesion composition and enhance atherosclerosis. Follow-up studies will test the effectiveness of reducing intracellular cholesterol levels in APOE2 bone marrow cells and reducing ER stress in APOE4 bone marrow cells in atherosclerosis protection. Aim 2 will transplant macrophage-depleted perivascular adipose tissues (PVAT) from APOE2 and APOE3 mice to the carotid arteries of Ldlr-/- mice to test the hypothesis that the dysfunctional APOE2 adipocytes recruit inflammatory cells to the PVAT tissue to promote inflammation, which in turn signals to the vasculature to enhance inflammatory cell recruitment to the lesion area to exacerbate atherosclerosis. Single-nucleus RNA-seq will be performed to compare how adipocyte-derived apoE2 and apoE3 influences adipocyte plasticity and elicit different immune cell repertoires to the PVAT and vasculature to modulate atherosclerosis. We will also test the hypothesis that increasing cholesterol efflux in APOE2 adipocytes will reduce inflammation and atherossclerosis. Novel mechanistic information gained from these studies can be harnessed to design personalized intervention strategies based on APOE genotype to reduce vascular diseases.

抽象的基于更好地理解特定遗传风险因素的其他新型治疗策略需要参与心血管疾病的发病机理和病理生理学才能进一步减少与这一主要死因有关的负担。心血管疾病的主要遗传危险因素是 APOE基因中的多态性。 APOE在许多细胞类型中合成，肝脏衍生的重要性维持血浆脂质稳态的APOE有充分的文献记载。 APOE（DYS）在其他单元中如何起作用类型影响动脉粥样硬化尚未完全描述。该项目的目的是确定如何在髓样细胞和脂肪细胞中表达的每个APOE变体都会影响动脉粥样硬化。初步结果表明：（i）来自人ApoE2和ApoE4基因置换小鼠的骨髓细胞的有效性较低比APOE3细胞减少APOE - / - 小鼠的动脉粥样硬化；（ii）APOE2和APOE4增强髓样细胞通过不同的机制炎症反应；（iii）ApoE2，但不是ApoE3或ApoE4脂肪细胞是功能障碍，细胞内胆固醇含量升高，可加速炎症和动脉粥样硬化。我们的前提是APOE2和APOE4通过不同的不同机制以及细胞类型特异性的方式，以加速动脉粥样硬化。我们的假设是apoe2 通过受损的细胞内胆固醇外排引起细胞功能障碍，而APOE4会导致髓样细胞功能障碍通过诱导氧化和ER应激。 AIM 1将检验髓样APOE2表达的假设增加骨髓卵并促进动脉粥样硬化的早期阶段，而髓样APOE4加速动脉粥样硬化的发展，由于其肿瘤病和代谢应激受损，因此到后期。单身的- 细胞RNA-seq将在病变平滑肌和免疫细胞上进行动脉粥样硬化至描述每个APOE在髓样细胞中的表达方式如何影响平滑肌细胞的塑性和病变免疫细胞库改变病变组成并增强动脉粥样硬化。后续研究将测试降低APOE2骨髓细胞中细胞内胆固醇水平的有效性并减少ER应力动脉粥样硬化保护中的APOE4骨髓细胞。 AIM 2将移植巨噬细胞的血管周围脂肪组织（PVAT）从APOE2和APOE3小鼠到LDLR - / - 小鼠的颈动脉，以检验假设功能失调的APOE2脂肪细胞将炎症细胞募集到PVAT组织以促进炎症，这又向脉管系统发出信号，以增强炎症细胞的募集到病变区域以加剧动脉粥样硬化。将进行单核RNA-Seq，以比较脂肪细胞衍生的APOE2和APOE3 影响脂肪细胞的可塑性并引起对PVAT和脉管系统的不同免疫细胞库调节动脉粥样硬化。我们还将检验以下假设：apoE2脂肪细胞中胆固醇外流增加将减少炎症和动脉粥样硬化。从这些研究中获得的新机械信息可以是利用基于APOE基因型的个性化干预策略来减少血管疾病。