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:
- 金额:$ 61.49万
- 依托单位:
- 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:
- 关键词:AdipocytesAdipose tissueAdrenal GlandsAgonistAllelesAlzheimer&aposs DiseaseApolipoprotein EAreaArterial Fatty StreakAtherosclerosisBiomedical ResearchBone Marrow CellsBone Marrow TransplantationBrainCETP geneCardiovascular DiseasesCarotid ArteriesCarotid Atherosclerotic DiseaseCause of DeathCell DeathCell NucleusCellsCholesterolCoronaryCoronary ArteriosclerosisDataDiabetes MellitusDietDiseaseE proteinExperimental Animal ModelExtrahepaticFollow-Up StudiesFunctional disorderGenesGenetic PolymorphismGenetic Population StudyGenotypeGoalsHepaticHepatocyteHomeostasisHumanHyperlipoproteinemia Type IIIImmuneImpairmentInflammasomeInflammationInflammatoryInflammatory ResponseInterventionKnock-outLeadLesionLipidsLipoproteinsLiverMetabolic dysfunctionMetabolic stressMusMutationMyelogenousMyeloid CellsMyelopoiesisNecrosisObesityOxidative StressPathogenesisPeripheral Vascular DiseasesPhasePlasmaPopulationPropertyRiskRisk FactorsRoleSeveritiesSignal TransductionSmooth MuscleSmooth Muscle MyocytesTestingTimeTissuesTransplantationTriglyceridesTunica AdventitiaVariantVascular Diseasesapolipoprotein E-3apolipoprotein E-4atherogenesisbasecardiovascular disorder riskcardiovascular risk factorcell typecytokinedesigneffectiveness testingendoplasmic reticulum stressgene replacementgenetic risk factorimprovedlipid metabolismmacrophagenon-diabeticnovelnovel therapeutic interventionoverexpressionpersonalized interventionpublic health relevancerecruitsingle-cell RNA sequencingsphingomyelin synthasetranscriptome sequencingwestern 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
其他新的治疗策略,基于更好地了解特定的遗传风险因素
参与心血管疾病的发病机制和病理生理学均有必要进一步减少
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
载脂蛋白E基因的多态性。载脂蛋白E是在多种细胞类型中合成的,而肝脏来源的重要性
载脂蛋白E在维持血脂平衡方面有很好的文献记载。ApoE(Dys)在其他细胞中如何发挥作用
类型对动脉粥样硬化的影响尚未完全阐明。该项目的目标是确定如何
在髓系细胞和脂肪细胞中表达的每个apoE变异体都会影响动脉粥样硬化。初步结果
结果表明:(I)来自人类APOE2和APOE4基因替换小鼠的骨髓细胞效果较差
APOE3细胞减少载脂蛋白E-/-小鼠动脉粥样硬化;(Ii)APOE2和apoE4促进髓系细胞
炎症反应通过不同的机制;和(Iii)APOE2,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。我们的
前提是载脂蛋白2和载脂蛋白E4通过不同的途径增强炎症和代谢功能障碍
以特定细胞类型的方式,加速动脉粥样硬化的机制。我们的假设是载脂蛋白2
通过受损的细胞内胆固醇外流导致细胞功能障碍,而apoE4导致髓系细胞
通过诱导氧化和内质网应激而导致的功能障碍。Aim 1将检验髓系APOE2表达的假设
增加骨髓生成并促进动脉粥样硬化的早期阶段,而髓系载脂蛋白E4加速
动脉粥样硬化进展到较晚阶段,是由于它的吞噬功能和代谢应激功能受损。单人-
在动脉粥样硬化的3个阶段,对病变的平滑肌和免疫细胞进行细胞RNA-seq
描述在髓系细胞中表达的每个apoE变异体如何影响平滑肌细胞的可塑性和损伤
改变病变成分和增强动脉粥样硬化的免疫细胞库。后续研究将测试
降低APOE2骨髓细胞内胆固醇水平及减轻内质网应激的作用
载脂蛋白E4骨髓细胞对动脉粥样硬化的保护作用。AIM 2将移植耗尽巨噬细胞的血管周围
从APOE2和APOE3小鼠的脂肪组织(PVAT)到LDLR-/-小鼠的颈动脉来验证这一假说
功能失调的APOE2脂肪细胞将炎性细胞招募到PVAT组织以促进炎症,
进而向血管系统发出信号,以加强炎症细胞对病变区域的募集,从而加剧
动脉硬化。将进行单核rna-seq以比较脂肪细胞衍生的apoE2和apoE3
影响脂肪细胞可塑性并诱导不同免疫细胞系对PVAT和血管系统的影响
调节动脉粥样硬化。我们还将测试增加APOE2脂肪细胞胆固醇流出的假设
会减少炎症和动脉粥样硬化。从这些研究中获得的新的机理信息可以
利用基于载脂蛋白E基因的个性化干预策略来减少血管疾病。
项目成果
期刊论文数量(0)
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David Yiu-Kwan Hui其他文献
David Yiu-Kwan Hui的其他文献
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{{ truncateString('David Yiu-Kwan Hui', 18)}}的其他基金
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
- 批准号:
10533337 - 财政年份:2021
- 资助金额:
$ 61.49万 - 项目类别:
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
- 批准号:
10167112 - 财政年份:2020
- 资助金额:
$ 61.49万 - 项目类别:
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
- 批准号:
10582114 - 财政年份:2019
- 资助金额:
$ 61.49万 - 项目类别:
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
- 批准号:
9761773 - 财政年份:2019
- 资助金额:
$ 61.49万 - 项目类别:
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
- 批准号:
10375435 - 财政年份:2019
- 资助金额:
$ 61.49万 - 项目类别:
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
- 批准号:
9889159 - 财政年份:2019
- 资助金额:
$ 61.49万 - 项目类别:
Intestinal LPC/LPA modulation of gut microbiota and metabolic disease
肠道 LPC/LPA 对肠道微生物群和代谢疾病的调节
- 批准号:
9354489 - 财政年份:2016
- 资助金额:
$ 61.49万 - 项目类别:
Role of Endothelial and Macrophage ApoER2 in Atherosclerosis Modulation
内皮细胞和巨噬细胞 ApoER2 在动脉粥样硬化调节中的作用
- 批准号:
9211369 - 财政年份:2014
- 资助金额:
$ 61.49万 - 项目类别:
Role of Endothelial and Macrophage ApoER2 in Atherosclerosis Modulation
内皮细胞和巨噬细胞 ApoER2 在动脉粥样硬化调节中的作用
- 批准号:
8794465 - 财政年份:2014
- 资助金额:
$ 61.49万 - 项目类别:
Role of Endothelial and Macrophage ApoER2 in Atherosclerosis Modulation
内皮细胞和巨噬细胞 ApoER2 在动脉粥样硬化调节中的作用
- 批准号:
8998064 - 财政年份:2014
- 资助金额:
$ 61.49万 - 项目类别:
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