Lung IDO-1+ TNFR2+ cDC2 subset in control of lung mucosal tolerance: Mechanism and Application
肺IDO-1 TNFR2 cDC2亚群控制肺粘膜耐受:机制和应用
基本信息
- 批准号:10322171
- 负责人:
- 金额:$ 44.95万
- 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:2021-01-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adoptive Cell TransfersAffectAllergicAllergic DiseaseAlveolarAmino AcidsAsthmaCaringCause of DeathCellsChemicalsChimeric ProteinsChronic Obstructive Pulmonary DiseaseChronic lung diseaseCuesDendritic CellsDevelopmentDisease ProgressionEnzymesEpithelialEpithelial CellsExtrinsic asthmaGoalsHealthcareHumanIFNAR1 geneImmuneImmune ToleranceImmune systemImpairmentInfectionInflammationInhalationInterferon-alphaKnockout MiceKnowledgeLungLung diseasesLung immune responseMHC Class II GenesMediatingMedicineMetabolicMolecularMonoclonal AntibodiesMucous MembraneMusOrganPathogenicityPatientsPersonsPopulationProductionProto-Oncogene Proteins c-aktPulmonary InflammationPyroglyphidaeRegimenRegulatory T-LymphocyteReportingResearchRoleSTAT1 geneSTAT3 geneSignal TransductionSourceSteroid ResistanceTNFRSF1B geneTherapeuticTherapeutic InterventionTryptophan 2,3 Dioxygenasealveolar type II cellarginaseautocrinebasechronic inflammatory lung diseaseconditional knockouteffective therapyimmunogenicimprovedin vivoinflammatory lung diseaseinhibitorinnovationmicrobiotamouse modelneutrophilparacrinepneumocytepreventprogramsrelapse patientsresponsetargeted treatmenttherapeutic targettranslational potential
项目摘要
Abstract
The lung is a natural tolerogenic organ. Lung mucosal tolerance must be exquisitely controlled by the lung
immune system to avoid the development of chronic inflammatory lung diseases. Our knowledge of lung
tolerance is, however, inadequate. This is evident in asthma treatments. Current asthma therapies are limited to
blunting the progression of the disease. Patients relapse once the treatments are stopped because the
treatments do not repair the underlying, dysregulated lung mucosal tolerance. Lung dendritic cells (DCs)
orchestrate lung immune responses. We recently reported a lung epithelial cells IFNβ-TNFR2+ cDC2 (R2D2) -
Tregs axis in control of lung tolerance. We further showed that lung R2D2 cells are plastic, which makes them
an ideal target for therapeutic intervention. The essential role of lung Tregs in maintaining tolerance has been
firmly established. In this proposal, we focus on i) uncovering the molecular and cellular mechanisms of the lung
epithelial cells IFNβ-R2D2 control of lung mucosal tolerance; ii) developing an IFNβ-based regimen to restore
lung tolerance in chronic inflammatory lung diseases. We showed, in this proposal, that lung alveolar type II cells
(AT-II) are the IFNβ+ cells, and STING is essential for basal IFNβ production in the lung. In Aim1, we will
determine the in vivo mechanism by which lung AT-II cells sustain lung IFNβ level and maintain lung tolerance
at the steady-state. In Aim2, we will determine the tolerogenic IFNβ program in mouse and human lung R2D2
cells. In Aim3, we will develop an IFNβ-based regimen to enhance, restore lung tolerance, and prevent, treat
inflammatory lung diseases in mice. Chronic inflammatory lung diseases are the 4th leading cause of death in
the U.S. Understanding the fundamental mechanism for lung tolerance and develop a new innovative regimen
to restore lung mucosal tolerance in chronic lung diseases are highly significant.
抽象的
肺是一种天然的耐受性器官。肺粘膜耐受性必须由肺部完全控制
免疫系统以避免慢性炎性肺部疾病的发展。我们对肺的了解
但是,宽容不足。这是哮喘治疗的证据。当前的哮喘疗法仅限于
使疾病的进展变得钝化。一旦停止治疗后,患者中继
治疗无法修复潜在的,失调的肺粘膜耐受性。肺树突状细胞(DC)
编排肺免疫调查。我们最近报道了肺上皮细胞IFNβ -TNFR2+ CDC2(R2D2) -
Tregs轴控制肺耐受性。我们进一步表明肺R2D2细胞是塑料的,这使得它们
热干预的理想目标。肺Treg在维持耐受性中的基本作用一直是
首先建立。在此提案中,我们关注i)揭示肺的分子和细胞机制
上皮细胞IFNβ-R2D2对肺粘膜耐受性的控制; ii)开发基于IFNβ的方案以恢复
慢性炎症性肺部疾病中的肺旅游。我们在此提案中表明,肺肺泡II型细胞
(AT-II)是IFNβ+细胞,刺激对于肺中的基本IFNβ产生至关重要。在AIM1中,我们将
确定肺AT-II细胞维持肺IFNβ水平并保持肺旅行的体内机制
在稳态。在AIM2中,我们将确定小鼠和人肺R2D2中的耐受性IFNβ程序
细胞。在AIM3中,我们将开发一种基于IFNβ的方案,以增强,恢复肺耐受性并预防,治疗
小鼠炎症性肺部疾病。慢性炎症性肺部疾病是第四大死亡原因
美国了解肺耐受性的基本机制,并开发一种新的创新疗法
恢复慢性肺部疾病中的肺粘膜耐受性非常重要。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('LEI JIN', 18)}}的其他基金
Lung IDO-1+ TNFR2+ cDC2 subset in control of lung mucosal tolerance: Mechanism and Application
肺IDO-1 TNFR2 cDC2亚群控制肺粘膜耐受:机制和应用
- 批准号:
10536690 - 财政年份:2021
- 资助金额:
$ 44.95万 - 项目类别:
Impact of Human STING Variants on Pneumococcal Vaccine Effectiveness
人类 STING 变体对肺炎球菌疫苗有效性的影响
- 批准号:
9165880 - 财政年份:2016
- 资助金额:
$ 44.95万 - 项目类别:
Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP
STING介导的环二-GMP粘膜疫苗佐剂活性机制
- 批准号:
8815747 - 财政年份:2014
- 资助金额:
$ 44.95万 - 项目类别:
Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP
STING介导的环二-GMP粘膜疫苗佐剂活性机制
- 批准号:
8880430 - 财政年份:2014
- 资助金额:
$ 44.95万 - 项目类别:
Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP
STING介导的环二-GMP粘膜疫苗佐剂活性机制
- 批准号:
8969663 - 财政年份:2014
- 资助金额:
$ 44.95万 - 项目类别:
Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP
STING 介导的环二 GMP 粘膜疫苗佐剂活性机制
- 批准号:
9185213 - 财政年份:2014
- 资助金额:
$ 44.95万 - 项目类别:
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