Targeting Estrogenic pathways in Tregs to promote ARDS resolution
Targeting Estrogenic pathways in Tregs to promote ARDS resolution
批准号:
10632120
负责人:
Franco R D'Alessio
金额:
$80.98万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-06-01 至 2026-05-31
关键词:
AcuteAcute PneumoniaAcute Respiratory Distress SyndromeAgonistAlveolarAnimalsAntiviral ResponseCOVID-19Candidate Disease GeneCause of DeathCell CountCell physiologyCellsCellular biologyClinicalClinical TrialsCritical PathwaysDataDevelopmentDisease modelElementsEstradiolEstrogen Receptor betaEstrogensFOXP3 geneFlow CytometryGATA3 geneGene ExpressionGene Expression ProfilingGenetic TranscriptionGoalsHomeostasisHumanImmuneImmune responseIn VitroInfectionInflammatoryInflammatory ResponseInjuryLungMacrophageMediatingMediatorModelingMolecularMusOutcomePathogenicityPathway interactionsPhasePilot ProjectsPlayPneumoniaPre-Clinical ModelProductionProteinsPublishingPulmonary InflammationRNA HelicaseRegulationRegulatory T-LymphocyteResolutionRoleSignal PathwaySignal TransductionStreptococcus pneumoniaeTestingTherapeuticTherapeutic EffectUp-RegulationVariantWorkacute infectionalveolar epitheliumantimicrobial resistant pathogencytokinedrug resistant pathogenestrogenichigh dimensionalityin silicoin vitro activityin vivoinflammatory lung diseaseloss of functionlung injurymortalityneutrophilnovel therapeuticspathogenpneumonia modelpneumonia treatmentpre-clinicalprogramspromoterrepairedresponsetherapeutic evaluationtherapeutic targettranscription factor
中文摘要
肺炎(PNA)是全球主要的死亡原因之一。PNA可导致毁灭性的急性
急性呼吸窘迫综合征(ARDS)表现为肺炎性损伤。目前的治疗方法
PNA专注于病原体,但不针对宿主免疫引发的过度肺部炎症
回应。以新冠肺炎为代表的新感染的出现,以及抗菌药的影响不断扩大
抗药性病原体,强调我们目前的医疗机构的局限性,并强调需要识别
PNA诱导的ARDS的其他治疗靶点。了解到PNA的解决是一种
积极调控计划以促进回归动态平衡,我们的工作重点是识别细胞和
这一拆分阶段的分子介体。其他人和我们已经证明了调节性T细胞(Tregs)
促进传染性ARDS的解决。
我们强大的初步数据已经确定了肺来源的Treg DHX58,它编码一种RNA解旋酶蛋白
对抗病毒反应至关重要,作为ARDS解决阶段上调的候选基因。DHX58-
肺炎链球菌-ARDS后,缺陷动物不能明显消退肺部炎症
在损伤解决过程中肺Treg数量减少,暗示DHX58在体内具有最佳Treg功能。此外,
我们观察到DHX58功能丧失变种携带者的30天死亡率显著增加
感染性ARDS(71%对47%,p=0.01),强调了DHX58在ARDS中的潜在临床影响
结果。我们对DHX58启动子的电子分析确定了许多雌激素反应元件(ERE)。
事实上,DHX58在Treg中的表达是由雌二醇(E2)诱导的。重要的是,我们发表的工作表明
治疗性E2以Treg依赖的方式促进临床前PNA-ARDS的解决。雌激素受体β
(ER)对Treg依赖的淋巴细胞减少宿主的拯救和Treg介导的抑制都是必需的
巨噬细胞体外促炎细胞因子的产生。初步的基因表达分析和高效的
三维流式细胞术研究E2及其下游靶点DHX58对临界Treg的调节作用
转录因子(TF),特别是Foxp3和GATA3。因此,我们假设E2部分是通过ER依赖的
DHX58的上调,通过调节键的表达来协调关键的Treg预解析功能
Tregs的TFS。这项提议的目标是确定细胞、分子和转录决定因素
E_2-ER-DHX58在Treg介导的PNA-ARDS的拆分中的作用
内质网在Tregs中的调节和功能作用
英文摘要
Pneumonia (PNA) is one of the leading causes of death worldwide. PNA can result in devastating acute
inflammatory injury in the lung manifesting in acute respiratory distress syndrome (ARDS). Current treatments for
PNA have focused on the pathogens, but do not target excessive lung inflammation elicited by the host immune
response. Both the emergence of new infections, typified by COVID-19, and the expanding impact of antimicrobial
resistant pathogens, highlight the limitations of our current armamentarium and underscore the need to identify
additional therapeutic targets in PNA-induced ARDS. With the understanding that resolution of PNA is an
actively regulated program to promote return to homeostasis, our work has focused on identifying cellular and
molecular mediators of this resolution phase. Others and we have demonstrated that regulatory T cells (Tregs)
promote resolution of infectious-ARDS.
Our strong preliminary data has identified lung-derived Treg DHX58, which encodes an RNA helicase protein
essential for antiviral responses, as a candidate gene upregulated during the resolution phase of ARDS. DHX58-
deficient animals fail to resolve lung inflammation after Streptococcus pneumoniae-ARDS with significantly
diminished lung Treg numbers during injury resolution, implicating DHX58 in optimal Treg function in vivo. Further,
we observed significantly increased 30-day mortality among carriers of a putative loss-of-function variant of DHX58
with infectious ARDS (71% vs. 47%, p=0.01), underscoring the potential clinical impact of DHX58 in ARDS
outcomes. Our in-silico analysis of the DHX58 promoter identified numerous estrogen responsive elements (ERE).
Indeed, DHX58 expression was induced in Tregs by estradiol (E2). Importantly, our published work showed that
therapeutic E2 promotes resolution of preclinical PNA-ARDS in a Treg-dependent manner. Estrogen receptor beta
(ER) was necessary for both Treg-dependent rescue of lymphopenic hosts and Treg-mediated suppression of
pro-inflammatory cytokine production in macrophages in vitro. Preliminary gene expression analysis and high-
dimensional flow cytometry implicate E2 and its downstream-target, DHX58, in the regulation of critical Treg
transcription factors (TFs), notably Foxp3 and GATA3. Thus, we hypothesize that E2, in part via ER-dependent
upregulation of DHX58, orchestrates critical Treg pro-resolution functions, through regulating expression of key
TFs in Tregs. The goals of this proposal are to determine the cellular, molecular and transcriptional determinants
of E2-ER-DHX58 in Treg-mediated resolution of PNA-ARDS to provide the mechanistic underpinnings of the
regulation and functional role of ER in Tregs.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3791/63925
发表时间:
2023
期刊:
Journal of visualized experiments : JoVE
影响因子:
--
作者:
[Villabona-Rueda,Andres, Wang,Daniel, D'Alessio,FrancoR]
通讯作者:
D'Alessio,FrancoR
Targeting Estrogenic pathways in Tregs to promote ARDS resolution
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批准号:10462918
-
项目类别:
-
资助金额:$81.63万
-
财政年份:2022
-
负责人:Franco R D'Alessio
-
依托单位:
Lung Injury Repair by Regulatory T cell LGP2
-
批准号:9309225
-
项目类别:
-
资助金额:$40.89万
-
财政年份:2017
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负责人:Franco R D'Alessio
-
依托单位:
Lung Injury Repair by Regulatory T cell Dhx58/LGP2
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批准号:9324420
-
项目类别:
-
资助金额:$40.75万
-
财政年份:2016
-
负责人:Franco R D'Alessio
-
依托单位:
Resolution and repair of acute lung injury by macrophage-derived iNOS
-
批准号:8539070
-
项目类别:
-
资助金额:$23.14万
-
财政年份:2010
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负责人:Franco R D'Alessio
-
依托单位:
Resolution and repair of acute lung injury by macrophage-derived iNOS
-
批准号:8669808
-
项目类别:
-
资助金额:$23.22万
-
财政年份:2010
-
负责人:Franco R D'Alessio
-
依托单位:
Resolution and repair of acute lung injury by macrophage-derived iNOS
-
批准号:8122310
-
项目类别:
-
资助金额:$13.64万
-
财政年份:2010
-
负责人:Franco R D'Alessio
-
依托单位:
Resolution and repair of acute lung injury by macrophage-derived iNOS
-
批准号:8527234
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2010
-
负责人:Franco R D'Alessio
-
依托单位:
Resolution and repair of acute lung injury by macrophage-derived iNOS
-
批准号:7953158
-
项目类别:
-
资助金额:$13.64万
-
财政年份:2010
-
负责人:Franco R D'Alessio
-
依托单位:
海外基金