IL-31 Regulation of Immunopathology in Pulmonary Fibrosis
IL-31 Regulation of Immunopathology in Pulmonary Fibrosis
批准号:
9762810
负责人:
Satish K Madala
金额:
$20.63万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-15 至 2021-04-30
关键词:
AffectAgingAnimalsBindingBleomycinBone MarrowBone Marrow CellsCellsCessation of lifeChronicClinicalCollagenComplexCytokine SignalingDataDevelopmentDiseaseDisease ProgressionFibroblastsFibrosisFutureGenesGenetic ModelsGenetic TranscriptionGoalsHeterogeneityHumanIn VitroIncidenceIndividualInflammationInterleukin-13Interleukin-4InterleukinsInterventionKnockout MiceKnowledgeLaboratoriesLesionLungLung diseasesMediatingMedicalModelingMusPathogenesisPathologicPathologyPathway interactionsPatientsPeripheral Blood Mononuclear CellPreventionPreventiveProductionPublishingPulmonary FibrosisPulmonary InflammationRegulationResearchRespiratory physiologyRoleSeveritiesSeverity of illnessSignal TransductionT cell responseT-LymphocyteT-Lymphocyte SubsetsTechniquesTestingTherapeuticTherapeutic InterventionValidationWild Type Mouseattenuationcytokinedisease phenotypefunctional declinehigh rewardhigh riskidiopathic pulmonary fibrosisimmunopathologyimprovedin vivoin vivo Modelinnovationmacrophagemouse modelnew therapeutic targetoncostatin Mpre-clinicalreceptor
中文摘要
项目总结
英文摘要
Project Summary
Idiopathic Pulmonary Fibrosis (IPF) affects approximately 5 million individuals worldwide and responsible for
40,00 deaths in the USA alone. Treatment for IPF is difficult, incomplete, and not curative. Th2-cytokine
polarized T cell responses are postulated to mediate inflammation, fibroblast activation, collagen production
and progressive fibrosis in IPF, yet there remains a wide knowledge gap on specific molecules involved in the
Th2 cytokine-driven immunopathology of IPF. Interleukin-31 (IL-31) is a newly identified cytokine produced by
activated Th2 T cells; however, the role of IL-31 in pulmonary inflammation and fibrosis has remained
unknown. IL-31 signals exclusively through a heterodimeric receptor complex consisting of IL-31 receptor
alpha (IL-31RA) and oncostatin M receptor beta (OSMRβ). Preliminary data from our laboratory show elevated
expression of IL-31, in the mature fibrotic lesions of IPF lungs and mouse model of bleomycin-induced
pulmonary fibrosis. Also, key Th-2 cytokines IL-4 and IL-13 directly increased IL-31RA expression in inflamed
macrophages and fibroblasts. Importantly, mice deficient in IL-31 signaling show attenuation of fibrosis and
improved lung function during bleomycin-induced pulmonary fibrosis. These findings support our central
hypothesis that IL-31-driven signaling contributes to the pathological remodelling and lung function
decline in IPF. The objective of this application is to identify the role of IL-31 in the immunopathogenesis of
IPF using both in vitro and in vivo models. Our long-term goal is to understand how the Th2 cytokines and IL-
31-IL-31RA interactions can be manipulated for preventive and therapeutic purposes in IPF. This hypothesis
will be tested by pursuing two specific aims: 1) determine the role of IL-31 in pulmonary fibrosis and lung
function decline using genetic models and reciprocal bone marrow cell transfers during bleomycin-induced
pulmonary fibrosis; and 2) identify IL-31 producing T cells and characterize IL-31-driven transcriptional
networks in IPF. The above aims will establish the role of IL-31 signaling and associated gene networks in
pulmonary fibrosis. Further, we will demonstrate that IL-31 is a new target for therapeutic interventions in IPF.
The approach is innovative by testing molecular interactions among IL-4, IL-13 and IL-31 and their cross-talk
using a mouse model of bleomycin-induced pulmonary fibrosis and knock-out mice. The proposed research is
significant, because completion of this study will increase our knowledge of the mechanisms causing IPF and
will lead to better medical treatments, cure or prevention.
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会议论文
Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis
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批准号:10180163
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项目类别:
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资助金额:$53.75万
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财政年份:2021
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负责人:Satish K Madala
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依托单位:
Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis
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批准号:10768171
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项目类别:
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资助金额:$49.55万
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财政年份:2021
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负责人:Satish K Madala
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依托单位:
Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis
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批准号:10620706
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项目类别:
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资助金额:$48.87万
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财政年份:2021
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负责人:Satish K Madala
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依托单位:
Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis
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批准号:10461725
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项目类别:
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资助金额:$3.7万
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财政年份:2021
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负责人:Satish K Madala
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依托单位:
WT1 REGULATION OF PULMONARY FIBROSIS
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批准号:10445452
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项目类别:
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资助金额:$53.03万
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财政年份:2017
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负责人:Satish K Madala
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依托单位:
WT1 REGULATION OF PULMONARY FIBROSIS
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批准号:9925244
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项目类别:
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资助金额:$38.99万
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财政年份:2017
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负责人:Satish K Madala
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依托单位:
WT1 REGULATION OF PULMONARY FIBROSIS
-
批准号:10770844
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项目类别:
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资助金额:$49.6万
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财政年份:2017
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负责人:Satish K Madala
-
依托单位:
WT1 REGULATION OF PULMONARY FIBROSIS
-
批准号:9214719
-
项目类别:
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资助金额:$40.92万
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财政年份:2017
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负责人:Satish K Madala
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依托单位:
THE ROLE OF IL-31 IN TH2 CYTOKINE-DRIVEN SYSTEMIC SCLEROSIS
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批准号:8850814
-
项目类别:
-
资助金额:$7.65万
-
财政年份:2013
-
负责人:Satish K Madala
-
依托单位:
THE ROLE OF IL-31 IN TH2 CYTOKINE-DRIVEN SYSTEMIC SCLEROSIS
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批准号:8446714
-
项目类别:
-
资助金额:$7.65万
-
财政年份:2013
-
负责人:Satish K Madala
-
依托单位:
海外基金