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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：
10363587
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/10363587
关键词：
Adipocytes Adipose tissue Adrenal Glands Agonist Alleles Alzheimer&apos s Disease Apolipoprotein E Area Arterial Fatty Streak Atherosclerosis Biomedical Research Bone Marrow Cells Bone Marrow Transplantation Brain CETP gene Cardiovascular Diseases Carotid Arteries Carotid Atherosclerotic Disease Cause of Death Cell Death Cell Nucleus 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 Population Study Genotype Goals Hepatic Hepatocyte Homeostasis Human Hyperlipoproteinemia Type III Immune Impairment Inflammasome Inflammation Inflammatory Inflammatory Response Intervention Knock-out Lead Lesion Lipids Lipoproteins Liver Metabolic dysfunction Metabolic stress Mus Mutation Myelogenous Myeloid Cells Myelopoiesis Necrosis Obesity Oxidative Stress Pathogenesis Peripheral Vascular Diseases Phase Plasma Population 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 base cardiovascular disorder risk cardiovascular risk factor cell type cytokine design effectiveness testing endoplasmic reticulum stress gene replacement genetic risk factor improved lipid metabolism macrophage non-diabetic novel novel therapeutic intervention overexpression personalized intervention public health relevance recruit single-cell RNA sequencing sphingomyelin synthase transcriptome sequencing 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.

摘要基于更好地理解特定遗传风险因素参与心血管疾病的发病机制和病理生理，有必要进一步减少与这一主要死因相关的负担。心血管疾病的一个主要遗传风险因素是 APOE基因的多态性ApoE在许多细胞类型中合成，载脂蛋白E在维持血浆脂质稳态中的作用已被充分证明。apoE（dys）在其他细胞中的作用型影响动脉粥样硬化尚未完全划定。这个项目的目标是确定如何在骨髓细胞和脂肪细胞中表达的每种apoE变体影响动脉粥样硬化。初步结果结果表明：（i）来自人APOE2和APOE4基因替代小鼠的骨髓细胞的有效性较低在ApoE-/-小鼠中，比APOE3细胞减少动脉粥样硬化;（ii）apoE 2和apoE 4增强骨髓细胞通过不同机制的炎症反应;和（iii）APOE2脂肪细胞，而不是APOE3或APOE4脂肪细胞，功能失调，细胞内胆固醇含量升高，加速炎症和动脉粥样硬化形成。我们前提是apoE2和apoE4通过不同的途径增强炎症和代谢功能障碍，机制，并以细胞类型特异性的方式，加速动脉粥样硬化。我们的假设是apoE 2 通过细胞内胆固醇流出受损导致细胞功能障碍，而apoE4导致骨髓细胞功能障碍通过诱导氧化和ER应激而导致功能障碍。目的1将检验髓系apoE2表达与骨髓细胞凋亡的关系。增加骨髓生成并促进动脉粥样硬化形成的早期阶段，而髓样apoE4加速动脉粥样硬化形成。动脉粥样硬化进展到后期，由于其损害的红细胞和代谢应激。单- 细胞RNA-seq将在动脉粥样硬化的3个阶段对病变平滑肌和免疫细胞进行，描述在髓样细胞中表达的每种apoE变体如何影响平滑肌细胞的可塑性和损伤免疫细胞库改变病变组成和增强动脉粥样硬化。后续研究将测试降低APOE 2骨髓细胞中细胞内胆固醇水平和降低ER应激的有效性骨髓细胞APOE4对动脉粥样硬化的保护作用目标2将移植去巨噬细胞的血管周围从APOE2和APOE3小鼠的脂肪组织（PVAT）到Ldlr-/-小鼠的颈动脉，以检验假设功能失调的APOE2脂肪细胞将炎性细胞募集到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向病变区域的募集动脉粥样硬化将进行单核RNA-seq，以比较脂肪细胞来源的apoE2和apoE3 影响脂肪细胞的可塑性，并引发不同的免疫细胞库的PVAT和脉管系统，调节动脉粥样硬化。我们还将检验增加APOE 2脂肪细胞中胆固醇流出的假设，将减少炎症和动脉粥样硬化。从这些研究中获得的新的机制信息可以根据APOE基因型设计个性化干预策略，以减少血管疾病。