NKA/CD36 signaling in adipocytes promotes oxidative stress and drives chronic inflammation in atherosclerosis
脂肪细胞中的 NKA/CD36 信号传导促进氧化应激并驱动动脉粥样硬化的慢性炎症
基本信息
- 批准号:10655793
- 负责人:
- 金额:$ 54.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:ATPase inhibitory proteinAdipocytesAdipose tissueAmino AcidsAnimal ModelApolipoprotein EArterial Fatty StreakArteriesAtherosclerosisAttenuatedBindingBiochemicalBiological AssayCD36 geneCause of DeathCellsChronicComplexDataDevelopmentDistantDyslipidemiasFoam CellsGene ExpressionGene Expression ProfilingGeneticGoalsHormonesIn VitroIncubatedInflammationInflammatoryInjectionsIonsK ATPaseKnockout MiceLabelLentivirus VectorLigandsLinkLipidsLocationMacrophageMacrophage ActivationMediatingMediatorMembraneMetabolicMethodsMicroRNAsMitochondriaModelingMolecularMolecular ConformationMusMyocardial InfarctionN DomainOxidative StressPathway interactionsPeptide Initiation FactorsPeptidesPhenotypePhosphotransferasesPlayProductionProteinsProteomePublishingPumpReagentReporterRisk FactorsRoleSignal TransductionStrokeStudy modelsTechniquesTestingTherapeuticTherapeutic InterventionTissuesWorkadipocyte biologyadipokinesatherogenesiscell typechronic inflammatory diseasecytokinediagnostic biomarkerdriving forceexosomeimmune activationimprovedin vivolimb ischemialimb losslipid metabolismlipidomelipidomicsmolecular phenotypemonocytemouse modelnew therapeutic targetnext generationnovelnovel diagnosticsnovel therapeutic interventionoxidant stressoxidized low density lipoproteinparacrinereceptorrelease factorresponsescaffoldscavenger receptorsrc-Family Kinasestraffickingtranscriptome sequencing
项目摘要
Atherosclerosis (AS) is a chronic inflammatory disease of medium and large arteries and remains the leading
cause of death worldwide from its sequelae of heart attack, stroke and limb loss. During AS progression
chronic activation of immune cells in the vessel wall, especially macrophages, leads to formation of lipid-loaded
foam cells which become the major component of atherosclerotic plaque. The goal is to discover molecular
mechanisms through which dyslipidemia and oxidative stress, which are major risk factors for AS, are linked to
chronic macrophage activation via dysregulated function of fat cells (adipocytes). The proposal will explore
how adipocyte-derived exosomes (Ad-Exo) carrying specific pro-atherogenic cargo such as miRNAs, are
generated under oxidative stress, and how they activate macrophages. Focus is CD36, type II scavenger
receptor highly expressed in adipocytes and macrophages that acts as a receptor for the atherogenic ligand
oxidized LDL (oxLDL). The oxLDL/CD36 signaling axis creates an inflammatory paracrine loop between
macrophages and adipocytes and facilitates oxidative stress and pro-inflammatory cytokine secretion through
Src family kinase (SFK) activation. Na/K-ATPase (NKA) α1 subunit serves both as a CD36 co- receptor and a
scaffold for the SFK, allowing conformational changes in the NKA to activate membrane bound SFK and
initiate signaling cascades, a mechanism distinct from its well-understood pumping function. Hypothesis of this
proposal is that activation of NKA/CD36 signaling in adipocytes produces oxidative stress that causes release
of adipokines and exosomes (Ad-Exo). These released factors initiate and augment AS by stimulating
macrophages. To test this hypothesis, 3 specific aims have been developed. The first will test the hypothesis
that adipocyte NKA/CD36 signaling complex promotes AS through production of cellular oxidative stress
leading to abnormal adipokines/exosome secretion. The approach will include use of the apoe null mouse
model and lentiviral vectors to deliver cell-specific NaKtide, a peptide reagent derived from the NKA α1 domain
that behaves as a specific inhibitor of the NKA/SFK pathway. Oxidant stress, AS plaque formation, and
adipocyte gene expression will be assessed using state-of-the-art techniques, such as next generation
RNASeq. The second aim will test whether Ad-Exo can modulate macrophage function in vitro and in vivo by
characterizing the proteome, lipidome and miRNA profile of Ad-Exo released in response to oxidative stress
and tracking their delivery to monocytes and AS plaque. A newly developed mouse model, GFP-
CD63flox/Adipoq Cre mice will be used as an excellent Ad-Exo reporter animal model for these studies. The
third aim will determine if Ad-Exo regulate macrophage lipid metabolism and mitochondrial function using
sophisticated metabolic flux assays along with lipidomic and gene expression assays. Successful completion
of this project will define an important concept that adipocyte CD36/NKA and downstream Ad-Exo secretion is
a driving force for chronic macrophage activation in AS, thereby identifying novel therapeutic targets.
动脉粥样硬化(AS)是一种中、大动脉慢性炎症性疾病,
它是世界范围内因心脏病发作、中风和肢体丧失后遗症而死亡的原因。AS进展期间
血管壁中免疫细胞,特别是巨噬细胞的慢性激活导致脂质负载的
泡沫细胞成为动脉粥样硬化斑块的主要成分。目标是发现分子
血脂异常和氧化应激是AS的主要危险因素,
通过脂肪细胞(脂肪细胞)功能失调而引起的慢性巨噬细胞活化。该提案将探讨
脂肪细胞来源的外泌体(Ad-Exo)携带特定的促动脉粥样硬化货物,如miRNA,
以及它们如何激活巨噬细胞。重点是CD 36,II型清道夫
在脂肪细胞和巨噬细胞中高度表达的受体,作为致动脉粥样硬化配体的受体
氧化低密度脂蛋白(oxLDL)。oxLDL/CD 36信号传导轴在细胞间产生炎性旁分泌环,
促进氧化应激和促炎细胞因子分泌,
Src家族激酶(SFK)激活。Na/K-ATP酶(NKA)α1亚基既作为CD 36辅助受体,又作为CD 38受体。
SFK的支架,允许NKA中的构象变化以激活膜结合的SFK,
启动信号级联,这是一种与其众所周知的泵功能不同的机制。对此的假设
建议是脂肪细胞中NKA/CD 36信号传导的激活产生氧化应激,
脂肪因子和外泌体(Ad-Exo)。这些释放出来的因子通过刺激动脉粥样硬化的发生,
巨噬细胞为了验证这一假设,已经制定了3个具体目标。第一个实验将检验这个假设
脂肪细胞NKA/CD 36信号复合物通过产生细胞氧化应激促进AS
导致异常的脂肪因子/外泌体分泌。该方法将包括使用apoe空小鼠
用于递送细胞特异性NaKtide(一种源自NKA α1结构域的肽试剂)的模型和慢病毒载体
其表现为NKA/SFK通路的特异性抑制剂。氧化应激、AS斑块形成和
脂肪细胞基因表达将使用最先进的技术,如下一代
RNASeq.第二个目的是通过以下方式测试Ad-Exo是否可以在体外和体内调节巨噬细胞功能:
表征响应于氧化应激释放的Ad-Exo的蛋白质组、脂质组和miRNA谱
并追踪它们向单核细胞和AS斑块的递送。一种新开发的小鼠模型,GFP-
CD 63 flox/Adipoq Cre小鼠将用作这些研究的优秀Ad-Exo报告基因动物模型。的
第三个目标将确定Ad-Exo是否调节巨噬细胞脂质代谢和线粒体功能,
复杂的代谢通量测定沿着脂质组学和基因表达测定。成功完成
本项目的研究将定义一个重要的概念,即脂肪细胞CD 36/NKA和下游Ad-Exo分泌是
AS中慢性巨噬细胞激活的驱动力,从而确定新的治疗靶点。
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 }}
Yiliang Chen其他文献
Yiliang Chen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 }}
相似国自然基金
支链氨基酸代谢紊乱调控“Adipocytes - Macrophages Crosstalk”诱发2型糖尿病脂肪组织功能和结构障碍的作用及机制
- 批准号:81970721
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
相似海外基金
Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
- 批准号:
321208980 - 财政年份:2016
- 资助金额:
$ 54.72万 - 项目类别:
Research Grants
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8827438 - 财政年份:2014
- 资助金额:
$ 54.72万 - 项目类别:
Induction of brown-like adipocytes in white adipose tissue by food-derived factors
食物源性因子在白色脂肪组织中诱导棕色样脂肪细胞
- 批准号:
26450168 - 财政年份:2014
- 资助金额:
$ 54.72万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
- 批准号:
257256526 - 财政年份:2014
- 资助金额:
$ 54.72万 - 项目类别:
Research Fellowships
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8828181 - 财政年份:2013
- 资助金额:
$ 54.72万 - 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8520690 - 财政年份:2013
- 资助金额:
$ 54.72万 - 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8629741 - 财政年份:2013
- 资助金额:
$ 54.72万 - 项目类别:
Effect of exercise training on formation of brite adipocytes within white adipose tissue
运动训练对白色脂肪组织内脂肪细胞形成的影响
- 批准号:
23700778 - 财政年份:2011
- 资助金额:
$ 54.72万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
- 批准号:
21780261 - 财政年份:2009
- 资助金额:
$ 54.72万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
- 批准号:
7610781 - 财政年份:2007
- 资助金额:
$ 54.72万 - 项目类别: