RvD1-FPR2 signaling ameliorates alcoholic liver disease
RvD1-FPR2信号传导可改善酒精性肝病
基本信息
- 批准号:10380761
- 负责人:
- 金额:$ 3.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2022-09-30
- 项目状态:已结题
- 来源:
- 关键词:AftercareAgonistAlcohol consumptionAlcoholic HepatitisAlcoholic Liver DiseasesAlcoholic steatohepatitisAlcoholsAnimal ModelAnimalsAnti-Bacterial AgentsBacteriaBiologyCell ExtractsCell physiologyCellsCessation of lifeChronicCirrhosisDataDisease modelDopamine D1 ReceptorEndotoxemiaEthanolExposure toFPR2 geneFatty LiverFibrosisFlow CytometryFutureGenesHepaticHistologicHumanImmuneImmune responseImmunologyInfectionInflammationInflammatory ResponseKupffer CellsLabelLeadLigandsLiverLiver diseasesMeasuresMediatingModelingMorbidity - disease rateMusPathogenesisPathogenicityPathologyPathway interactionsPatientsPhagocytesPhagocytosisPlasmaPlayPopulationPrognosisProteomicsReceptor ActivationReceptor CellRegimenResolutionRespiratory BurstRoleSamplingSampling StudiesSerumSeveritiesSignal PathwaySignal TransductionStimulusTherapeuticTissuesWorkalcohol exposureantimicrobialbasechronic liver diseasecytokinedefense responsefeedinghealthy volunteerlipid mediatorliver inflammationliver injurymacrophagemonocytemortalityneutrophilnovel markernovel therapeutic interventionphosphoproteomicspreventresponsestandard caretreatment strategy
项目摘要
Alcoholic hepatitis (AH) is a morbid condition with poor prognosis that is primarily driven by altered
immune cell function in response to endotoxemia, but the mechanisms are not fully known or
understood. Resolvin D1 (RvD1) is a pro-resolution lipid mediator that signals through formyl
peptide receptor 2 (FPR2) in mice eliciting M2 polarization in macrophages and antibacterial
functions in neutrophils. Plasma RvD1 levels and hepatic FPR2 expression are decreased in AH
patients suggesting this pathway is impeded in AH. Animal models suggest RvD1 treatment
ameliorates alcohol induced liver injury, inflammation, fibrosis, and endotoxemia while Fpr2-/- mice
develop exacerbated liver injury, inflammation, fibrosis, and endotoxemia. Studies characterizing
the RvD1-FPR2 signaling pathway in alcoholic liver disease (ALD) are nonexistent but are
warranted based on preliminary data. Aim 1: This aim will determine if RvD1 acts solely through
FPR2 to elicit protection in an animal of alcoholic liver disease (ALD). Aim 2: Aim 2a will determine
if the RvD1-FPR2 signaling pathway is essential for M2 polarization of Kupffer cells. Aim 2b will
establish if RvD1-FPR2 signaling is required for neutrophil-mediated defense responses against
pathogenic threats. Aim 3: AH patient and healthy control acquired neutrophils and monocytes
will be treated with or without RvD1 ex vivo followed by flow cytometry and proteomic and
phosphoproteomic analysis to measure receptor activation and to characterize the signaling
pathway, respectively. Collectively this study will generate data that could identify RvD1 or FPR2
agonists as a therapeutic approach for ALD. Due to the severity of AH and the analysis of AH
patient samples this study it is immediately impactful and informative for future treatment
strategies. Novel biomarkers and therapeutic interventions are expected to come from the
conclusion of the proposed study. Basic biology of the RvD1-FPR2 signaling pathway in
neutrophils and monocytes is expected from this work as well.
酒精性肝炎(AH)是一种预后不佳的病态疾病,主要由酒精性肝炎引起
免疫细胞功能对内毒素血症的反应,但其机制尚不完全清楚
明白了。分解蛋白D_1(RvD_1)是一种通过甲酰基传递信号的促分解脂类介体
小鼠肽受体2(FPR2)引起巨噬细胞M2极化及抗菌作用
中性粒细胞的功能。急性脑出血患者血浆RvD1水平和肝脏FPR2表达降低
提示此通路在急性肝炎中受阻的患者。动物模型建议Rvd1治疗
改善Fpr2-/-小鼠酒精性肝损伤、炎症、纤维化和内毒素血症
出现加重的肝损伤、炎症、纤维化和内毒素血症。研究的特点
RvD1-FPR2信号通路在酒精性肝病(ALD)中是不存在的
根据初步数据是有根据的。目标1:这一目标将决定Rvd1是否仅通过
FPR2诱导对酒精性肝病(ALD)动物的保护作用。目标2:目标2a将决定
RvD1-FPR2信号通路对Kupffer细胞M2极化是必不可少的。目标2b将
确定中性粒细胞介导的防御反应是否需要RvD1-FPR2信号转导
致病威胁。目的3:获得性中性粒细胞和单核细胞
将接受或不接受RvD1的体外治疗,随后进行流式细胞仪和蛋白质组学和
磷蛋白质组学分析测量受体激活并表征信号转导
途径,分别为。总而言之,这项研究将产生可以识别Rvd1或FPR2的数据
激动剂作为ALD的一种治疗方法。由于急性呼吸窘迫的严重性和对急性呼吸暂停的分析
患者对这项研究进行了抽样,它立即产生了影响,并为未来的治疗提供了信息
战略。新的生物标记物和治疗干预有望来自
拟议研究的结论。RvD1-FPR2信号通路的基础生物学研究
中性粒细胞和单核细胞也有望从这项工作中获得。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Liver-specific drug delivery platforms: Applications for the treatment of alcohol-associated liver disease.
- DOI:10.3748/wjg.v28.i36.5280
- 发表时间:2022-09-28
- 期刊:
- 影响因子:4.3
- 作者:Warner JB;Guenthner SC;Hardesty JE;McClain CJ;Warner DR;Kirpich IA
- 通讯作者:Kirpich IA
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{{ truncateString('Josiah E Hardesty', 18)}}的其他基金
Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH
肝心磷脂水平的恢复和保存促进 AH 中的肝再生
- 批准号:
10708057 - 财政年份:2022
- 资助金额:
$ 3.26万 - 项目类别:
Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH
肝心磷脂水平的恢复和保存促进 AH 中的肝再生
- 批准号:
10572240 - 财政年份:2022
- 资助金额:
$ 3.26万 - 项目类别:
RvD1-FPR2 signaling ameliorates alcoholic liver disease
RvD1-FPR2信号传导可改善酒精性肝病
- 批准号:
10160633 - 财政年份:2020
- 资助金额:
$ 3.26万 - 项目类别:
Polychlorinated biphenyls act through EGFR to worsen NAFLD
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9328668 - 财政年份:2017
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