Neuro-immune regulation of intestinal inflammation
肠道炎症的神经免疫调节
基本信息
- 批准号:10670215
- 负责人:
- 金额:$ 63.7万
- 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:2020-09-17 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:Adoptive Cell TransfersAffectAllergicAllergic inflammationAmericanAmphiregulinAttenuatedBiological ProductsBiologyBiopsyBone Marrow SuppressionCell CommunicationCell LineageCell physiologyCellsChemical ModelsChemicalsChronicChronic DiseaseClinicalColonCrohn&aposs diseaseCytometryDataDevelopmentDiarrheaDiseaseEconomic BurdenEconomicsEnteralEnvironmental Risk FactorEpidermal Growth Factor ReceptorFamilyFlow CytometryGeneticGenetic TranscriptionHealthcare SystemsHelminthsHemorrhageHomeostasisHumanImageImmuneImmunityIndividualInflammationInflammatoryInflammatory Bowel DiseasesInjuryIntegration Host FactorsIntestinal parasiteIntestinesKineticsLigandsLymphoid CellMalignant NeoplasmsMeasuresMediatingMicroscopyMolecularMucous MembraneMusMuscle CrampNervous SystemNeuroimmuneNeuromedin UNeuronsNeuropeptidesOpportunistic InfectionsPainPancreatitisPathway interactionsPatientsPatternPersonsPharmaceutical PreparationsPhysiologicalPopulationProductionProliferatingPropertyPublic HealthPulmonary InflammationQuality of lifeRegulationReporterRiskRoleSignal PathwaySignal TransductionSodium Dextran SulfateSourceSpatial DistributionStimulusSurfaceTSLP geneTestingTherapeuticTissuesTreatment CostUlcerative ColitisUnited StatesUp-Regulationassociated symptomattenuationcostcytokinegastrointestinalgut inflammationimprovedin vivoinjury and repairinsightintestinal injuryliver inflammationmicrobialmicrobiotamouse modelneuromedin U receptornew therapeutic targetnovelnovel therapeuticspre-clinicalrepairedresponsetissue repair
项目摘要
PROJECT SUMMARY
Inflammatory bowel diseases, which include both ulcerative colitis and Crohn's disease, are estimated to affect
3 million Americans, and the number of people living with IBD continues to rise. Currently available
medications are costly, ineffective for some patients, and associated with serious risks including opportunistic
infections, bone marrow suppression, hepatic inflammation, pancreatitis, and cancer. Thus, there is an urgent
need to improve our understanding of modulators of intestinal inflammation and repair in order to identify novel
therapeutic targets for the treatment of IBD. Innate lymphoid cells (ILCs) are a relatively-recently characterized
family of immune cells that are enriched at barrier surfaces and modulate inflammation in response to cytokine
and microbial signals. In particular, group 2 ILCs (ILC2s) sense alarmins and cytokines such as IL-25, IL-33,
and TSLP, can be activated by the nervous system, and produce type 2 cytokines that promote anti-helminth
immunity and allergic inflammation. Furthermore, our lab has shown that ILC2s also exert tissue-protective
functions via secretion of the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG), resulting
in amelioration of tissue damage following intestinal injury. In new preliminary studies presented here, we show
that expression of the neuropeptide, neuromedin U (NMU), is increased during intestinal inflammation in mice,
and lack of endogenous NMU results in more severe disease in a model of chemical-induced intestinal
damage and inflammation. Conversely, therapeutic administration of NMU results in upregulation of ILC2-
derived AREG and ameliorates chemical-induced intestinal damage. Furthermore, similar to in inflamed murine
intestines, NMU expression is also elevated in IBD patient biopsies, and the receptor for NMU is detected on
human colonic ILCs. Based on our new preliminary data, we hypothesize that enteric neuron-derived NMU
activates the tissue-protective functions of ILC2s. We propose to generate a detailed understanding of how
NMU mediates tissue protection in both murine models of intestinal inflammation and human IBD. In Aim 1, we
will test the hypothesis that during intestinal injury and repair, expression, cellular sources, and spatial pattern
of NMU expression are altered. We will also test the role of endogenous enteric-derived NMU in maintaining
tissue homeostasis. In Aim 2, we will employ novel reporter mice to directly test the cellular and molecular
mechanism by which NMU mediates tissue protection. In Aim 3, we will define the NMU-NMUR1 axis in the
healthy human intestine and determine how alterations in NMU-NMUR1 signaling correlate with clinical and
endoscopic measures of IBD disease activity. In addition to uncovering fundamental and novel neuropeptide
biology and their unique roles in IBD, these studies will provide preclinical justification for development of novel
therapeutics to target this pathway.
项目总结
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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David Artis其他文献
David Artis的其他文献
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{{ truncateString('David Artis', 18)}}的其他基金
Dietary Regulation of Intestinal Inflammation and Repair
肠道炎症和修复的饮食调节
- 批准号:
10592429 - 财政年份:2022
- 资助金额:
$ 63.7万 - 项目类别:
Microbiota-derived metabolites and the regulation of host immunity and inflammation
微生物群衍生的代谢物以及宿主免疫和炎症的调节
- 批准号:
10512805 - 财政年份:2022
- 资助金额:
$ 63.7万 - 项目类别:
Microbiota-derived metabolites and the regulation of host immunity and inflammation
微生物群衍生的代谢物以及宿主免疫和炎症的调节
- 批准号:
10645229 - 财政年份:2022
- 资助金额:
$ 63.7万 - 项目类别:
Neuropeptide-mediated regulation of antihelminth immunity
神经肽介导的抗蠕虫免疫调节
- 批准号:
10120198 - 财政年份:2020
- 资助金额:
$ 63.7万 - 项目类别:
Neuropeptide-mediated regulation of antihelminth immunity
神经肽介导的抗蠕虫免疫调节
- 批准号:
10468776 - 财政年份:2020
- 资助金额:
$ 63.7万 - 项目类别:
Neuro-immune regulation of intestinal inflammation
肠道炎症的神经免疫调节
- 批准号:
10462650 - 财政年份:2020
- 资助金额:
$ 63.7万 - 项目类别:
Neuropeptide-mediated regulation of antihelminth immunity
神经肽介导的抗蠕虫免疫调节
- 批准号:
10265558 - 财政年份:2020
- 资助金额:
$ 63.7万 - 项目类别:
Neuropeptide-mediated regulation of antihelminth immunity
神经肽介导的抗蠕虫免疫调节
- 批准号:
10681244 - 财政年份:2020
- 资助金额:
$ 63.7万 - 项目类别:
Neuro-immune regulation of intestinal inflammation
肠道炎症的神经免疫调节
- 批准号:
10097714 - 财政年份:2020
- 资助金额:
$ 63.7万 - 项目类别:
Neuro-immune regulation of intestinal inflammation
肠道炎症的神经免疫调节
- 批准号:
10264888 - 财政年份:2020
- 资助金额:
$ 63.7万 - 项目类别:
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