Type III interferon Control of Mucosal Immunity
III 型干扰素控制粘膜免疫
基本信息
- 批准号:10587625
- 负责人:
- 金额:$ 77.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAmphiregulinAntiviral ResponseApoptosisBacteriaBiochemicalBiological ModelsBiopsyCOVID-19 patientCell DeathCell LineCellsChronicColitisCritical IllnessDataDefectDevelopmentDiseaseEnteralEnvironmentEnvironmental Risk FactorEpithelial CellsEpitheliumEquilibriumEtiologyExposure toFamilyFlareGastrointestinal tract structureGenesGeneticGenetic TranscriptionGoalsHomeostasisHumanImmune responseImmune systemInfectionInflammationInflammatoryInflammatory Bowel DiseasesInterferon Type IInterferon Type IIInterferonsIntestinesKnowledgeLamina PropriaLinkLungMendelian disorderMolecularMucosal ImmunityMucous MembraneMusMutationNamesOrganoidsPaneth CellsPathogenesisPathogenicityPatientsPhasePlayProductionProliferatingPropertyProteinsReceptor SignalingRegulationRoleSignal TransductionSmall IntestinesStimulusSurfaceTherapeuticTherapeutic InterventionTimeTissuesVariantViralViral PhysiologyVirusVirus Diseasescell typeearly childhoodgastrointestinal epitheliumhealinghuman modelhuman tissueinfancyinflammatory modulationinsightintestinal epitheliumirradiationmembermicrobialmicrobial communitymicrobiotamouse modelmurine colitismutantneutrophilnew therapeutic targetnovelnovel therapeutic interventionpreventprogramsreceptor expressionrepairedresponsespatiotemporalsystemic inflammatory responsetherapeutically effectivetissue repairvirome
项目摘要
The capacity of the immune system to govern repair after tissue damage is fundamental to protect the host
against infections. The gastrointestinal tract represents an ideal tissue to explore the mechanisms underlying
the exquisite balance between tissue damage and repair. Inflammatory bowel diseases (IBDs) are a group of
heterogenous disorders, associated with contributing genetic and environmental factors, that are characterized
by inflammatory phases kept in balance by tissue repair. Although the etiology of IBDs is not clear, a hallmark of
these inflammatory diseases is a chronic and dysregulated immune response. Despite significant progress in
elucidating the mechanisms that govern tissue damage, the mechanistic underpinnings controlling how the
immune system affects the restitution phase following IBD flares have not been thoroughly explored. Interferons
(IFNs) are key players during an immune response and are increased in IBD. IFNs belong to three families: type
I, type II, and type III (also known as IFN-λ) IFNs. Type I IFNs and IFN-λ play potent anti-viral roles, both inducing
a similar set of IFN stimulated genes (ISGs) that were believed to play only redundant roles. We recently
challenged this paradigm and showed that IFNλ, but not type I IFNs, limits inflammation during murine colitis by
dampening the tissue damaging functions of neutrophils. In keeping with a key role of IFN-λ in tuning
inflammation in the gut and in maintaining a healthy intestinal environment, we have recently identified two
unrelated IBD patients presenting in infancy that have rare-damaging mutations in IFN-λs that lead to defective
IFN-λ receptor signaling. This potential novel monogenic disorder links directly for the first-time defects in anti-
viral regulation with IBD pathogenesis. Although IFN-λ has anti-viral properties and limits inflammation and tissue
damage, the involvement of this group of IFNs during tissue restitution of the gut is more controversial. In keeping
with a detrimental role of IFN-λ at mucosal surfaces, we have recently demonstrated that IFNλ delays
proliferation and favors apoptosis of lung epithelial cells in mouse models of persistent viral infections and in
critically ill COVID-19 patients. By investigating the activity of IFNλ in multiple mouse models of intestinal
damage, we now revealed a new molecular cascade initiated by IFNλ in intestinal epithelial cells that culminates
in a form of cell death called pyroptosis. Our data demonstrate that IFNλ delays gut restitution. We hypothesize
that along the intestinal tract, IFNλ can play opposing roles during IBD. Although IFNλ dampens tissue damage,
it can delay tissue restitution because of its compartmentalized action on either neutrophils or IECs. Employing
murine and human model systems and human tissue, our goal is to decipher the mechanistic basis for both the
pathogenic and protective roles of IFNλ and to identify new therapeutic targets. To reach our goals we will
address: i) What drives the production of IFNλ, and which cells produce, or respond to, IFNλ; ii) What are the
components of the signaling cascade that controls pyroptosis induction in IECs; iii) How the production of IFNλ
is regulated during early childhood and how it impacts IBD development in patients.
免疫系统控制组织损伤后修复的能力对于保护宿主至关重要
防止感染。胃肠道是探索其潜在机制的理想组织
组织损伤与修复之间的微妙平衡。炎症性肠病(IBD)是一组
异质性疾病,与遗传和环境因素有关,其特征是
通过组织修复保持平衡的炎症阶段。尽管 IBD 的病因尚不清楚,但 IBD 的一个特点是
这些炎症性疾病是一种慢性且失调的免疫反应。尽管取得了重大进展
阐明控制组织损伤的机制,控制组织损伤的机制基础
免疫系统对 IBD 发作后恢复阶段的影响尚未得到彻底探索。干扰素
(IFN) 在免疫反应过程中发挥着关键作用,并且在炎症性肠病 (IBD) 中会增加。干扰素属于三个家族: 类型
I、II 型和 III 型(也称为 IFN-λ)干扰素。 I 型 IFN 和 IFN-λ 发挥有效的抗病毒作用,均诱导
一组类似的干扰素刺激基因(ISG)被认为只发挥多余的作用。我们最近
挑战了这一范式,并表明 IFNλ(而非 I 型 IFN)通过以下方式限制小鼠结肠炎期间的炎症:
抑制中性粒细胞的组织损伤功能。与 IFN-λ 在调节中的关键作用保持一致
肠道炎症和维持健康的肠道环境,我们最近发现了两种
不相关的 IBD 患者在婴儿期就诊,其 IFN-λ 具有罕见的破坏性突变,导致缺陷
IFN-λ 受体信号传导。这种潜在的新型单基因疾病与抗肿瘤药物的首次缺陷直接相关。
病毒调控与 IBD 发病机制。尽管 IFN-λ 具有抗病毒特性并限制炎症和组织
损伤,这组干扰素在肠道组织恢复过程中的参与更具争议性。为了保持
由于 IFN-λ 在粘膜表面具有有害作用,我们最近证明 IFN-λ 会延迟
在持续病毒感染的小鼠模型和小鼠模型中,促进肺上皮细胞增殖并促进其凋亡
重症 COVID-19 患者。通过研究多种小鼠肠道模型中 IFNλ 的活性
损伤,我们现在揭示了肠上皮细胞中由 IFNλ 引发的新分子级联反应,该级联反应最终达到顶峰
以一种称为焦亡的细胞死亡形式。我们的数据表明 IFNλ 会延迟肠道恢复。我们假设
沿着肠道,IFNλ 在 IBD 期间可以发挥相反的作用。尽管 IFNλ 可以抑制组织损伤,
它可以延迟组织恢复,因为它对中性粒细胞或 IEC 具有分隔作用。雇用
小鼠和人类模型系统和人体组织,我们的目标是破译两者的机制基础
IFNλ 的致病和保护作用并确定新的治疗靶点。为了实现我们的目标,我们将
地址:i) 是什么驱动 IFNλ 的产生,以及哪些细胞产生或响应 IFNλ; ii) 什么是
控制 IEC 中细胞焦亡诱导的信号级联的组成部分; iii) IFNλ如何产生
在儿童早期受到监管以及它如何影响患者 IBD 的发展。
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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Scott B Snapper其他文献
Efficacy and Safety of Anti-Tumor Necrosis Factor Alpha in Very Early Onset Inflammatory Bowel Disease.
抗肿瘤坏死因子α在极早发炎症性肠病中的功效和安全性。
- DOI:
10.1093/ibd/izad196 - 发表时间:
2023 - 期刊:
- 影响因子:4.9
- 作者:
L. Collen;V. Mitsialis;David Y. Kim;Mairead Bresnahan;Jessica Yang;M. Tuthill;A. Combs;J. Barends;M. Field;Enju Liu;R. Bearup;I. Okoroafor;Christoph Klein;A. Muise;A. Bousvaros;J. Ouahed;Scott B Snapper - 通讯作者:
Scott B Snapper
Discordance between a deep learning model and clinical-grade variant pathogenicity classification in a rare disease cohort
罕见疾病队列中深度学习模型与临床级变异致病性分类之间的不一致
- DOI:
10.1101/2024.05.22.24307756 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
S. Kong;In;Lauren V Collen;Arjun K Manrai;Scott B Snapper;Kenneth D Mandl - 通讯作者:
Kenneth D Mandl
Scott B Snapper的其他文献
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{{ truncateString('Scott B Snapper', 18)}}的其他基金
Employing novel humanized murine strains to develop hematopoietic stem cell gene therapeutic approaches for very early-onset inflammatory bowel disease due to IL10-receptor deficiency.
采用新型人源化小鼠品系开发造血干细胞基因治疗方法,用于治疗因 IL10 受体缺陷所致的极早发炎症性肠病。
- 批准号:
9535567 - 财政年份:2017
- 资助金额:
$ 77.74万 - 项目类别:
Exploring Regulatory T Cell Dysfunction in a Murine Model of Colitis
探索小鼠结肠炎模型中的调节性 T 细胞功能障碍
- 批准号:
8232674 - 财政年份:2011
- 资助金额:
$ 77.74万 - 项目类别:
Deciphering the Role of WASP Family Proteins in T Cell Function
解读 WASP 家族蛋白在 T 细胞功能中的作用
- 批准号:
8147996 - 财政年份:2010
- 资助金额:
$ 77.74万 - 项目类别:
Exploring Regulatory T Cell Dysfunction in a Murine Model of Colitis
探索小鼠结肠炎模型中的调节性 T 细胞功能障碍
- 批准号:
7877475 - 财政年份:2009
- 资助金额:
$ 77.74万 - 项目类别:
Cytoskeletal-Pathogen Interactions in Shigella Infection
志贺氏菌感染中的细胞骨架-病原体相互作用
- 批准号:
6800508 - 财政年份:2003
- 资助金额:
$ 77.74万 - 项目类别:
Cytoskeletal-Pathogen Interactions in Shigella Infection
志贺氏菌感染中的细胞骨架-病原体相互作用
- 批准号:
6833455 - 财政年份:2003
- 资助金额:
$ 77.74万 - 项目类别:
Cytoskeletal-Pathogen Interactions in Shigella Infection
志贺氏菌感染中的细胞骨架-病原体相互作用
- 批准号:
7161772 - 财政年份:2003
- 资助金额:
$ 77.74万 - 项目类别:
Cytoskeletal-Pathogen Interactions in Shigella Infection
志贺氏菌感染中的细胞骨架-病原体相互作用
- 批准号:
6630241 - 财政年份:2003
- 资助金额:
$ 77.74万 - 项目类别:
Cytoskeletal-Pathogen Interactions in Shigella Infection
志贺氏菌感染中的细胞骨架-病原体相互作用
- 批准号:
7012813 - 财政年份:2003
- 资助金额:
$ 77.74万 - 项目类别:
The Pathogenesis Of Colitis In A Novel Th2 Model Of IBD
新型 IBD Th2 模型中结肠炎的发病机制
- 批准号:
6418028 - 财政年份:2002
- 资助金额:
$ 77.74万 - 项目类别:
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