Role of IgE in Atherosclerosis
IgE 在动脉粥样硬化中的作用
基本信息
- 批准号:8448117
- 负责人:
- 金额:$ 40.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-09-15 至 2016-02-29
- 项目状态:已结题
- 来源:
- 关键词:Acute myocardial infarctionAdoptive TransferAffinityAllergic ReactionAngina PectorisAntibodiesApolipoprotein EApoptosisApoptoticAreaArterial Fatty StreakAtherosclerosisBindingBlocking AntibodiesBlood PlateletsBlood VesselsCell Culture TechniquesCell DeathCell physiologyCellsChestComplexControl AnimalCoronary heart diseaseDataDendritic CellsDepositionDietEndothelial CellsExposure toFoam CellsFunctional disorderFundingHumanHyperlipidemiaHypersensitivityIgEIgE ReceptorsImmunoblot AnalysisImmunologyImmunoprecipitationIn VitroInfectionInflammationInflammation MediatorsInflammatoryInflammatory ResponseInterruptionKnock-outLesionLigandsLipidsLipopolysaccharidesLow Density Lipoprotein ReceptorM cellMacrophage ActivationMediatingMitogen-Activated Protein KinasesMolecularMusNHE1NecrosisParasitesPathogenesisPathway interactionsPatientsPlant RootsPlasma CellsProcessProductionResistanceRoleSerumSignal TransductionSmall Interfering RNASmooth Muscle MyocytesStimulusSurfaceTLR2 geneTestingToll-like receptorsUnstable anginaUrsidae FamilyVascular Diseasesabdominal aortaalanylglycineallergic responseaortic archatherogenesisbasecell typechemokinecytokineeosinophilethylisopropylamilorideextracellularin vivoinhibitor/antagonistmacrophagemast cellmonocytenovelomalizumaboxidized low density lipoproteinparticlereceptorreconstitutionresearch studyresponsetoll-like receptor 4
项目摘要
DESCRIPTION (provided by applicant): Immunoglobulin E (IgE) associates with allergic responses, but we found that its serum levels are enhanced in patients with acute myocardial infarction or unstable angina pectoris; they are nearly double those in patients with stable angina pectoris or without coronary heart disease. Both IgE and its high-affinity receptor Fc¿R1 were expressed highly in human atherosclerotic lesions, localized to areas rich in macrophages (M¿), and colocalized to lesion smooth-muscle cells (SMCs) and endothelial cells (ECs). Preliminary experiments showed that in the absence of Fc¿R1 ¿-subunit, atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice developed 75% fewer lipid depositions in the thoracic-abdominal aorta and had a >50% reduction in atherosclerotic lesion sizes in the aortic arch, compared with Apoe-/- control mice. In vitro cell culture studies demonstrated that IgE induced activation of M¿, SMC, and EC mitogen-activated protein kinase (MAPK) pathway, along with enhanced inflammatory molecule production and apoptosis. Surprisingly, IgE stimulated a complex formation between Fc¿R1 ¿-chain and Toll-like receptor 4 (TLR4). Both Fc¿R1 ¿-subunit and TLR4 are necessary for IgE-induced M¿ cytokine and chemokine expression and apoptosis. Furthermore, these activities of IgE on M¿ associate with activation of Na+-H+ exchanger NHE1, followed by extracellular pH reduction. These novel preliminary findings are consistent with prior observations that in human atherosclerotic lesions, apoptotic cells cluster around lipid-rich necrotic cores, where the pH values are significantly lower (pH 7.15¿0.01) than in other areas of the same lesions (pH 7.55¿0.32, P=0.0001). Therefore, we hypothesize that IgE contributes to atherosclerosis by regulating M¿, vascular SMC, and EC inflammation and apoptosis, and that these processes depend on Fc¿R1 and TLR4 interaction as well as on NHE1 activation. We propose two specific aims to test this hypothesis: 1). To examine the molecular mechanisms by which IgE stimulates M¿ and vascular SMC and EC inflammation and apoptosis. 2). To examine whether inhibition or deficiency of IgE or IgE receptor Fc¿R1 reduces atherosclerosis, and to test the importance of IgE-mediated M¿ activation in atherogenesis. We anticipate that the experiments proposed in both aims will establish an important and novel role of IgE in M¿ and vascular cell pathobiology, and a direct participation of IgE in atherogenesis.
描述(由适用提供):免疫球蛋白E(IgE)与过敏反应相关,但我们发现急性心肌梗塞或不稳定心绞痛的患者的血清水平得到了增强。它们几乎是稳定心绞痛患者或没有冠状动脉疾病的患者的两倍。 IgE及其高亲和力受体FC¿R1在人动脉粥样硬化病变中均高度表达,位于富含巨噬细胞(M?)的区域,并将其共定位于病变平滑肌细胞(SMCS)和内皮细胞(ECS)。 Preliminary experiments showed that in the absence of Fc¿ R1 ¿ -subunit, atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice developed 75% fewer lipid depositions in the thoracic-abdominal aorta and had a >50% reduction in atherosclerotic lesion sizes in the aortic arch, compared with Apoe-/- control mice.体外细胞培养研究表明,IgE诱导了M?,SMC和EC有丝分裂原激活的蛋白激酶(MAPK)途径的激活,以及增强的炎症分子的产生和凋亡。出乎意料的是,IgE刺激了Fc?r1链和类似Toll样受体4(TLR4)之间的复杂形成。 Fc¿r1� -subunit和tlr4对于IgE诱导的M¿细胞因子和趋化因子的表达和凋亡都是必需的。此外,IgE上的这些活性与Na+ -H+交换器NHE1的激活相关,然后是细胞外pH还原。这些新的初步发现与先前的观察结果一致,即在人动脉粥样硬化病变中,凋亡细胞聚集在富含脂质的坏死核周围,其中pH值明显低(pH 7.15€0.0.01)(pH 7.15€0.01)比在同一病变的其他区域(pH 7.55€7.0.32,p = 0.0001)。因此,我们假设IgE通过调节M,血管SMC以及EC炎症和凋亡有助于动脉粥样硬化,并且这些过程取决于FCCOR1和TLR4的相互作用以及NHE1激活。我们提出了两个特定的目的来检验这一假设:1)。检验IgE刺激M?,血管SMC以及EC炎症和凋亡的分子机制。 2)。为了检查IgE或IgE受体FC¿R1的抑制作用或缺乏会减少动脉粥样硬化,并测试IgE介导的M介导在动脉粥样硬化中的重要性。我们预计,在两个目标中提出的实验将确立IgE在M€和血管细胞病理生物学中的重要和新作用,以及IgE在动脉粥样硬化中的直接参与。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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GUO-PING SHI其他文献
GUO-PING SHI的其他文献
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{{ truncateString('GUO-PING SHI', 18)}}的其他基金
Role of group 2 innate lymphoid cells in myocardial infarction
第 2 组先天淋巴细胞在心肌梗死中的作用
- 批准号:
10365354 - 财政年份:2021
- 资助金额:
$ 40.47万 - 项目类别:
Role of group 2 innate lymphoid cells in myocardial infarction
第 2 组先天淋巴细胞在心肌梗死中的作用
- 批准号:
10540759 - 财政年份:2021
- 资助金额:
$ 40.47万 - 项目类别:
Role of ILC2 and eosinophils in abdominal aortic aneurysm
ILC2 和嗜酸性粒细胞在腹主动脉瘤中的作用
- 批准号:
10322053 - 财政年份:2021
- 资助金额:
$ 40.47万 - 项目类别:
Role of ILC2 and eosinophils in abdominal aortic aneurysm
ILC2 和嗜酸性粒细胞在腹主动脉瘤中的作用
- 批准号:
10538557 - 财政年份:2021
- 资助金额:
$ 40.47万 - 项目类别:
Role of a novel IL18 binding protein in atherosclerosis
新型 IL18 结合蛋白在动脉粥样硬化中的作用
- 批准号:
8882740 - 财政年份:2015
- 资助金额:
$ 40.47万 - 项目类别:
Role of a novel IL18 binding protein in atherosclerosis
新型 IL18 结合蛋白在动脉粥样硬化中的作用
- 批准号:
9130248 - 财政年份:2015
- 资助金额:
$ 40.47万 - 项目类别:
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