Epithelial chitinase and lung homeostasis
上皮几丁质酶和肺稳态
基本信息
- 批准号:9262267
- 负责人:
- 金额:$ 39.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAllelesAllergicAllergic inflammationAntigensAppearanceArthropodsAspergillusAspirate substanceAttenuatedBacteriaBindingBreathingBronchoalveolar LavageCarbohydratesCellsCellularityCelluloseChitinChitin SynthaseChitinaseChronicCollagenD CellsDictyopteraDiseaseEnvironmentEnzymesEosinophiliaEpithelialEpitheliumExposure toExtrinsic allergic alveolitisFibrosisGrantHamman-Rich syndromeHomeostasisHost DefenseHouse DustHouse miceHumanImageImmunityImpairmentIn SituInfiltrationInflammationInflammatory InfiltrateInjuryInsectaInterleukin-1Interleukin-13Interleukin-13 OverexpressionInterleukin-17Interleukin-5Interleukin-7InvertebratesKnockout MiceLectinLifeLungLung InflammationLung diseasesLymphocyteLymphoid CellMediatingModelingMorphogenesisMusNutrientOrganOrganismPathway interactionsPhenotypePlantsPlayPolymersPolysaccharidesProcessProductionPulmonary FibrosisPyroglyphidaeReporterResistanceResolutionRespiratory physiologyRoleSignal TransductionStomachStructure of respiratory bronchioleSyndromeTLR4 geneTNF geneTSLP geneTimeTissuesTransgenic MiceVertebratesacidic mammalian chitinaseasthmatic patientattenuationbasecytokineeosinophilfungusgene replacementgenetic linkageinsightinterleukin-23lung injurymacrophageneutrophilnovel therapeuticsparticlepathogenpublic health relevanceresponseγδ T cells
项目摘要
DESCRIPTION (provided by applicant): The lung is exposed to many environmental challenges throughout life, and further information is needed about secreted moieties that serve to sustain homeostasis. We generated mice that lack an epithelial enzyme necessary to degrade environmental polysaccharides widely prevalent in the environment. After polysaccharide challenge, these mice sustain prolonged lung inflammation associated with activation of Group 2 innate lymphoid cells (ILC2s) and lung gamma-delta T cells that release cytokines, including IL-5 and IL-13, and IL-17, respectively. The resultant inflammatory infiltrate including neutrophils and eosinophils, cause lung damage that can be overcome when epithelial enzymatic activity is restored. Unexpectedly, these knockout mice developed spontaneous lung inflammation over 6-9 months, even when maintained in a pathogen-free facility. Inflammation included fibrosis, most prominent around medium airways, and was characterized by enhanced tissue cellularity and increased lung collagen. As such, these mice provide a spontaneous model for pulmonary fibrosis due to activation of innate lung lymphoid cells and over-expression of IL-13 and IL-7, two cytokines previously implicated in prior models of provoked organ and tissue fibrosis. We have generated a number of genetically marked reporter mice to follow the relevant cells and cytokines, which will be used to unravel the mechanisms underlying this fibrosing phenotype. The grant proposes to study the lung phenotype in three Specific Aims. 1. To establish the role for lung ILC2 cells to determine whether these cells and IL-13 play an injury-promoting or injury-attenuating role. 2. To establish the role for lung gamma-delta cells to
determine the role these cells and IL-17 play in the phenotype. 3. To establish the mechanism by which the lung disposes of insoluble environmental polysaccharides. Humans contain the same enzyme in robust amounts in bronchoalveolar lavage, suggesting evolutionary conservation of this pathway for lung homeostasis. Our studies may have relevance to understanding modifiers of chronic fibrosing syndromes of humans, such as idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis, conditions for which further pathogenetic insights are needed.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Richard M Locksley其他文献
Richard M Locksley的其他文献
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{{ truncateString('Richard M Locksley', 18)}}的其他基金
ILC2 and epithelial cell heterogeneity and self-sustaining type 2 airway niches in asthma
ILC2 和上皮细胞异质性以及哮喘中自我维持的 2 型气道生态位
- 批准号:
10472534 - 财政年份:2012
- 资助金额:
$ 39.63万 - 项目类别:
ILC2 and epithelial cell heterogeneity and self-sustaining type 2 airway niches in asthma
ILC2 和上皮细胞异质性以及哮喘中自我维持的 2 型气道生态位
- 批准号:
10681273 - 财政年份:2012
- 资助金额:
$ 39.63万 - 项目类别:
ILC2 and epithelial cell heterogeneity and self-sustaining type 2 airway niches in asthma
ILC2 和上皮细胞异质性以及哮喘中自我维持的 2 型气道生态位
- 批准号:
10226876 - 财政年份:2012
- 资助金额:
$ 39.63万 - 项目类别:
ILC2 and epithelial cell heterogeneity and self-sustaining type 2 airway niches in asthma
ILC2 和上皮细胞异质性以及哮喘中自我维持的 2 型气道生态位
- 批准号:
10006351 - 财政年份:2012
- 资助金额:
$ 39.63万 - 项目类别:
Innate and Adaptive Immune Cell Cross-Talk in Lung Allergy
肺部过敏中的先天性和适应性免疫细胞交叉对话
- 批准号:
7476187 - 财政年份:2008
- 资助金额:
$ 39.63万 - 项目类别:
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