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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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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