Role of Interferon lambda signaling in mucosal homeostasis and infantile-onset inflammatory bowel disease
干扰素 lambda 信号传导在粘膜稳态和婴儿发病炎症性肠病中的作用
基本信息
- 批准号:10675638
- 负责人:
- 金额:$ 16.8万
- 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:2020-09-30 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:5 year old6 year oldAcuteAgeAge MonthsAwardBiological AssayBiopsyCell Culture TechniquesCellsChildColitisDataDevelopmentDiagnosisDiseaseEpithelial CellsEpitheliumEquipoiseExperimental ModelsExposure toFunctional disorderGastrointestinal tract structureGenerationsGenesGeneticGenetic Predisposition to DiseaseGenomicsGoalsGut MucosaHIVHematopoieticHepatitis BHomeostasisHumanIFNGR1 geneImmuneImmune signalingImpairmentIn VitroIncidenceInfantInflammatory Bowel DiseasesInheritedInterferon Type IInterferon Type IIInterferon alphaInterferonsIntestinesLifeLinkMentorsModelingMolecularMucous MembraneMusMutationNorth AmericaOrganoidsOxidative StressPathway interactionsPatientsPatternPeripheral Blood Mononuclear CellPhysiciansPlayPredispositionPrevalenceProductionProliferatingReportingRoleSARS-CoV-2 P.1ScientistSeveritiesSignal TransductionStructureTechnologyTherapeuticTherapeutic UsesTimeTissuesTrainingTranslatingVariantViralViral PhysiologyVirusVirus DiseasesWild Type MouseWorkcareer developmentcausal variantcell typecurative treatmentscytokineearly onsetefficacy evaluationexperiencefunctional genomicsgut homeostasisgut inflammationhealingimmune functionimprovedin vivoinfancyintestinal barrierintestinal epitheliumintestinal homeostasismicrobiomemicrobiome componentsmicroorganismmurine colitisnovelnovel strategiespreventreceptorresponsesingle-cell RNA sequencingskillstooltranscriptome sequencingvirome
项目摘要
PROJECT SUMMARY/ABSTRACT
The gastrointestinal tract is composed of a single layer of epithelial cells that is in equipoise with immune cells
and a vast number of microorganisms. Inappropriate responses to these microorganisms, either through
genetic predisposition, altered immune or epithelial responses, or yet to be defined environmental influences,
are postulated to lead to inflammatory bowel diseases (IBD). The immune signals that recognize and respond
to bacterial and viral components of the microbiome remain incompletely understood. Interferons (IFNs) play a
major role in antiviral immune defense in the intestinal epithelium, and are also important in regulating
proliferation, differentiation, survival and effector functions of immune and non-immune cells. There are three
classes of IFNs: type I IFNs (IFNα, β, and others), type II IFN (IFNγ) and type III IFNs, or IFNλs. To date, most
studies investigating the use of IFNs on IBD have focused on type I IFNs and were not found to be effective.
Dr. Ivan Zanoni recently reported that IFNλ decreases oxidative stress and intestinal damage in a murine
model of colitis and that exogenous IFNλ can suppress intestinal inflammation. Importantly, we identified two
unrelated patients with infantile-onset IBD with rare and functionally deleterious mutations in IFNλ2 and IFNλ3.
Of note, each patient's disease improved significantly with age. We have preliminary data that IFNλ2 and
IFNλ3 may be more important in the first months of life than FNλ1, and data illustrating more severe murine
colitis in Ifnλ3-/- mice as compared to wild type mice. Taken together, we hypothesize that INFλs are
essential modulators of mucosal homeostasis, prevent development of IBD, and hold therapeutic
potential. Current therapeutics available for the management of IBD fail to treat a large number of patients.
This work will provide a better understanding of the role of IFNλ in mucosal homeostasis, and may provide the
groundwork to implement novel strategies to treat IBD by manipulating IFNλ signaling. Unraveling the role of
IFNλ in maintaining mucosal homeostasis will be achieved through the following aims: (1) Establishing the
developmental expression of IFNλs, related cytokines and receptors in humans at different ages using bulk
and single cell RNA sequencing technologies (2) Determining the role of IFNλ signaling in predisposition to
development of colitis in vivo using various murine models of colitis; (3) Characterizing the functional
consequences of patient-encoded IFNλ variants in vitro using T84 cells as well as human control and patient-
derived intestinal organoids. This award will enable Dr. Ouahed to acquire necessary structured training to
become proficient in critical skills: RNAseq analysis, murine models of colitis and immune analyses, and
generation/manipulation of intestinal organoids and epithelial analyses, complimented with didactic
coursework, assisting her path to independence as a successful physician-scientist.
项目摘要/摘要
胃肠道由与免疫细胞平衡的单层上皮细胞组成。
以及大量的微生物。对这些微生物的不适当反应,要么通过
遗传易感性,免疫或上皮性反应改变,或尚未确定的环境影响,
被认为会导致炎症性肠病(IBD)。识别和响应的免疫信号
对微生物组的细菌和病毒成分的了解仍然不完全。干扰素(IFN)发挥作用
在肠道上皮细胞的抗病毒免疫防御中起主要作用,也在调节
免疫和非免疫细胞的增殖、分化、存活和效应功能。一共有三个
干扰素类:I型干扰素(干扰素α,β等)、II型干扰素(干扰素γ)和III型干扰素,或干扰素λS。
研究使用IFN治疗IBD的研究主要集中在I型IFN上,但没有发现有效。
伊万·扎诺尼博士最近报道,干扰素λ可减少小鼠的氧化应激和肠道损伤
结肠炎模型,外源性干扰素λ可抑制肠道炎症。重要的是,我们确定了两个
无血缘关系的婴儿起病的炎症性疾病患者,其干扰素λ2和干扰素λ3基因突变罕见且对功能有害。
值得注意的是,每个患者的病情都随着年龄的增长而显著改善。我们有初步数据显示干扰素λ2和
干扰素λ3在生命的最初几个月可能比FNλ1更重要,数据表明更严重的小鼠
干扰素λ3-/-小鼠与野生型小鼠的结肠炎。综上所述,我们假设λS是
粘膜动态平衡的基本调节剂,预防IBD的发展,并保持治疗
潜力。目前可用于治疗IBD的治疗方法无法治疗大量患者。
这项工作将有助于更好地理解干扰素λ在粘膜动态平衡中的作用,并可能为
通过操纵干扰素λ信号实现治疗炎症性肠病的新策略的基础工作。解开中国的角色
干扰素λ维持粘膜动态平衡的作用将通过以下目标来实现:(1)建立
不同年龄人群干扰素λ、S及相关细胞因子和受体的发育性表达
和单细胞核糖核酸测序技术(2)确定干扰素λ信号在易感性中的作用
使用不同的小鼠结肠炎模型在体内发展结肠炎;(3)表征功能性
患者编码的干扰素λ变体在体外使用T84细胞以及人类对照和患者-
衍生的肠道器官。这一奖项将使瓦赫德博士能够获得必要的系统培训,以
精通关键技能:RNAseq分析、小鼠结肠炎模型和免疫分析,以及
肠道器官和上皮分析的产生/操作,与说教相配
作为一名成功的内科科学家,帮助她走上了独立的道路。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease.
- DOI:10.3389/fimmu.2022.1026511
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:
- 通讯作者:
Expanding Contributions of Monogenic Very Early Onset Inflammatory Bowel Disease.
单基因极早发炎症性肠病的影响不断扩大。
- DOI:10.1093/ibd/izab145
- 发表时间:2021
- 期刊:
- 影响因子:4.9
- 作者:Ouahed,Jodie
- 通讯作者:Ouahed,Jodie
Pediatric Gastrointestinal Histopathology in Patients With Tetratricopeptide Repeat Domain 7A (TTC7A) Germline Mutations: A Rare Condition Leading to Multiple Intestinal Atresias, Severe Combined Immunodeficiency, and Congenital Enteropathy.
四肽重复结构域7A(TTC7A)种系突变患者的小儿胃肠道组织病理学:一种罕见的疾病,导致多个肠闭锁,严重的合并免疫缺陷和先天性肠胃疾病。
- DOI:10.1097/pas.0000000000001856
- 发表时间:2022-06-01
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
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Jodie Ouahed其他文献
Jodie Ouahed的其他文献
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{{ truncateString('Jodie Ouahed', 18)}}的其他基金
Role of Interferon lambda signaling in mucosal homeostasis and infantile-onset inflammatory bowel disease
干扰素 lambda 信号传导在粘膜稳态和婴儿发病炎症性肠病中的作用
- 批准号:
10534008 - 财政年份:2020
- 资助金额:
$ 16.8万 - 项目类别:
Role of Interferon lambda signaling in mucosal homeostasis and infantile-onset inflammatory bowel disease
干扰素 lambda 信号传导在粘膜稳态和婴儿发病炎症性肠病中的作用
- 批准号:
10189574 - 财政年份:2020
- 资助金额:
$ 16.8万 - 项目类别:
Role of Interferon lambda signaling in mucosal homeostasis and infantile-onset inflammatory bowel disease
干扰素 lambda 信号传导在粘膜稳态和婴儿发病炎症性肠病中的作用
- 批准号:
10456091 - 财政年份:2020
- 资助金额:
$ 16.8万 - 项目类别:
Role of Interferon lambda signaling in mucosal homeostasis and infantile-onset inflammatory bowel disease
干扰素 lambda 信号传导在粘膜稳态和婴儿发病炎症性肠病中的作用
- 批准号:
9976675 - 财政年份:2020
- 资助金额:
$ 16.8万 - 项目类别:
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