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
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APOE 2和APOE 4基因替代小鼠的骨髓细胞的有效性较低
在ApoE-/-小鼠中,比APOE 3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)APOE 2脂肪细胞,而不是APOE 3或APOE 4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apoE 2和apoE 4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
通过受损的细胞内胆固醇流出导致细胞功能障碍,而apoE 4导致骨髓细胞
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apoE 2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apoE 4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。单身-
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APOE 4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APOE 2和APOE 3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APOE 2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apoE 2和apoE 3
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。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
David Yiu-Kwan Hui其他文献
David Yiu-Kwan Hui的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Deciphering the role of adipose tissue in common metabolic disease via adipose tissue proteomics
通过脂肪组织蛋白质组学解读脂肪组织在常见代谢疾病中的作用
- 批准号:
MR/Y013891/1 - 财政年份:2024
- 资助金额:
$ 61.49万 - 项目类别:
Research Grant
ESTABLISHING THE ROLE OF ADIPOSE TISSUE INFLAMMATION IN THE REGULATION OF MUSCLE MASS IN OLDER PEOPLE
确定脂肪组织炎症在老年人肌肉质量调节中的作用
- 批准号:
BB/Y006542/1 - 财政年份:2024
- 资助金额:
$ 61.49万 - 项目类别:
Research Grant
Activation of human brown adipose tissue using food ingredients that enhance the bioavailability of nitric oxide
使用增强一氧化氮生物利用度的食品成分激活人体棕色脂肪组织
- 批准号:
23H03323 - 财政年份:2023
- 资助金额:
$ 61.49万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of new lung regeneration therapies by elucidating the lung regeneration mechanism of adipose tissue-derived stem cells
通过阐明脂肪组织干细胞的肺再生机制开发新的肺再生疗法
- 批准号:
23K08293 - 财政年份:2023
- 资助金额:
$ 61.49万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Canadian Alliance of Healthy Hearts and Minds: Dissecting the Pathways Linking Ectopic Adipose Tissue to Cognitive Dysfunction
加拿大健康心灵联盟:剖析异位脂肪组织与认知功能障碍之间的联系途径
- 批准号:
479570 - 财政年份:2023
- 资助金额:
$ 61.49万 - 项目类别:
Operating Grants
Determinants of Longitudinal Progression of Adipose Tissue Inflammation in Individuals at High-Risk for Type 2 Diabetes: Novel Insights from Metabolomic Profiling
2 型糖尿病高危个体脂肪组织炎症纵向进展的决定因素:代谢组学分析的新见解
- 批准号:
488898 - 财政年份:2023
- 资助金额:
$ 61.49万 - 项目类别:
Operating Grants
A study on the role of brown adipose tissue in the development and maintenance of skeletal muscles
棕色脂肪组织在骨骼肌发育和维持中作用的研究
- 批准号:
23K19922 - 财政年份:2023
- 资助金额:
$ 61.49万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
A mechanism of lipid accumulation in brown adipose tissue
棕色脂肪组织中脂质积累的机制
- 批准号:
10605981 - 财政年份:2023
- 资助金额:
$ 61.49万 - 项目类别:
Obesity and Childhood Asthma: The Role of Adipose Tissue
肥胖和儿童哮喘:脂肪组织的作用
- 批准号:
10813753 - 财政年份:2023
- 资助金额:
$ 61.49万 - 项目类别:
Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation
下丘脑腹内侧区的雌激素信号调节脂肪组织代谢适应
- 批准号:
10604611 - 财政年份:2023
- 资助金额:
$ 61.49万 - 项目类别: