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.
项目概要
炎症性肠病,包括溃疡性结肠炎和克罗恩病,估计会影响
300 万美国人,患有 IBD 的人数持续增加。目前可用
药物治疗费用昂贵,对某些患者无效,并且存在严重风险,包括机会性风险
感染、骨髓抑制、肝脏炎症、胰腺炎和癌症。因此,有一个紧急的
需要提高我们对肠道炎症和修复调节剂的理解,以便识别新的
IBD 治疗的治疗靶点。先天淋巴细胞 (ILC) 是一种相对较新的特征
免疫细胞家族,在屏障表面富集并响应细胞因子调节炎症
和微生物信号。特别是,第 2 组 ILC (ILC2) 可感知警报素和细胞因子,例如 IL-25、IL-33、
和TSLP,可以被神经系统激活,产生促进抗蠕虫的2型细胞因子
免疫和过敏性炎症。此外,我们的实验室已表明 ILC2 还发挥组织保护作用
通过分泌表皮生长因子受体 (EGFR) 配体双调蛋白 (AREG) 发挥作用,从而产生
改善肠道损伤后的组织损伤。在这里提出的新的初步研究中,我们表明
小鼠肠道炎症期间神经肽神经调节素 U (NMU) 的表达增加,
在化学诱导的肠道模型中,缺乏内源性 NMU 会导致更严重的疾病
损伤和炎症。相反,NMU 的治疗性给药会导致 ILC2- 的上调
衍生的 AREG 并改善化学引起的肠道损伤。此外,类似于发炎的小鼠
在肠道中,IBD 患者活检中 NMU 表达也升高,并且在肠道中检测到 NMU 受体
人类结肠 ILC。根据我们新的初步数据,我们假设肠神经元衍生的 NMU
激活 ILC2 的组织保护功能。我们建议详细了解如何
NMU 在小鼠肠道炎症模型和人类 IBD 模型中介导组织保护。在目标 1 中,我们
将检验以下假设:在肠道损伤和修复过程中,表达、细胞来源和空间模式
NMU 表达发生改变。我们还将测试内源性肠源性 NMU 在维持
组织稳态。在目标2中,我们将使用新型报告小鼠来直接测试细胞和分子
NMU 介导组织保护的机制。在目标 3 中,我们将在
健康人肠道并确定 NMU-NMUR1 信号传导的改变如何与临床和
IBD 疾病活动的内窥镜测量。除了发现基本的和新颖的神经肽
生物学及其在 IBD 中的独特作用,这些研究将为新型药物的开发提供临床前依据。
针对该途径的治疗。
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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