Gut Intrinsic Inflammatory Responses
肠道内在炎症反应
基本信息
- 批准号:10614624
- 负责人:
- 金额:$ 44.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-26 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAntigen-Presenting CellsAntigensAutoantigensAutomobile DrivingBiological AssayCell Differentiation processCellsChemicalsCollectionDevelopmentDietEarly identificationEcosystemEpithelial CellsEpitheliumEquilibriumEventExposure toFlow CytometryGastrointestinal tract structureGene ExpressionGenerationsGnotobioticGoblet CellsHomeostasisImmuneImmune responseImmune systemImmunityImmunologicsInfectionInflammatoryInflammatory Bowel DiseasesInflammatory ResponseInjuryLamina PropriaMapsMicrobeModelingMonitorMucous body substanceMusPathogenesisPathogenicityPathway interactionsPhenotypePhysiologicalProcessPropertyRegulatory T-LymphocyteReporterRoleSeveritiesSmall Intestinal Goblet CellSmall IntestinesSpecificitySurfaceT-LymphocyteT-cell receptor repertoireTransgenic Miceadaptive immune responsechronic inflammatory diseasecytokinedietaryenteric infectiongut inflammationin vivoinsightintestinal epitheliummicrobialmicrobiotamicroorganism antigennovel strategiespathogenresponsetransdifferentiation
项目摘要
The gastrointestinal (GI) tract is a large surface lined by a single layer epithelium which is exposed
to trillions of microbes and innocuous substances from the diet. The largest collection of immune
cells in the body underlies this single layer epithelium and monitors the luminal contents to
maintain tolerance to dietary and commensal antigens in the steady-state while retaining the
ability to rapidly induce immunity to pathogens during infection. While great progress has been
made in elucidating the role(s) of specific immune cell subsets, cytokines, and other factors
promoting tolerance or immunity, the processes intrinsic to the gut that enable the immune system
to switch from an overwhelmingly tolerogenic tone in the steady-state to inflammatory responses
during infection remains a gap in our understanding. Recently, we have uncovered that inhibiting
goblet cell associated antigen passages (GAPs) in the small intestine (SI) rapidly shifts the
immunologic tone away from tolerance and promotes the rapid induction of inflammatory Th17
responses in the absence of infection or injury. We hypothesize that the inhibition of GAPs is a
physiologic response to enteric infection, which in and of itself, promotes the generation of Th17
cells and inflammatory cytokines and shifts the tone of the immune system away from tolerance
toward immunity. By studying this process in the absence of enteric infection or injury we can
disentangle contributions of the pathogen and injury to the inflammatory response from intrinsic
properties of the gut ecosystem promoting the switch from a tolerogenic to pro-inflammatory state.
Understanding intrinsic properties of the gut that allows the rapid generation of protective
responses could provide new approaches to treat enteric infections and provide insight into the
pathogenesis of chronic inflammatory diseases of the gut. We hypothesize that when SI GAPs
are inhibited, other pathways take over driving the development and/or expansion of Th17 cells
specific for dietary, microbial, and/or self antigens, which shifts the tone of the immune system to
provide enhanced protection during enteric infection and/or injury. To explore this hypothesis we
propose the following specific aims: In aim 1 we will identify the early events resulting in Th17
expansion following SI GAP inhibition, in aim 2 we will define the origins and specificities of the
Th17 cells that expand when SI GAPs are inhibited in aim 3 we will determine if the inhibition of
SI GAPs is protective in models of enteric infection and whether inappropriate inhibition of SI
GAPs potentiates intestinal inflammatory disease.
胃肠道(GI)是一个大的表面,内衬单层上皮细胞,
食物中的数万亿微生物和无害物质。最大的免疫集合
体内的细胞位于这一单层上皮细胞之下,并监测腔内容物,
维持对稳定状态的饮食和肠道抗原的耐受性,同时保持
在感染期间迅速诱导对病原体的免疫的能力。虽然取得了很大进展,
在阐明特定的免疫细胞亚群、细胞因子和其他因子的作用时,
促进耐受性或免疫力,肠道固有的过程使免疫系统
从稳定状态下压倒性的致耐受性转变为炎症反应
在我们的理解中仍然存在差距。最近,我们发现抑制
小肠(SI)中的杯状细胞相关抗原通道(GAP)迅速改变了
免疫调节远离耐受,促进炎症性Th 17的快速诱导
在没有感染或损伤的情况下的反应。我们假设间隙的抑制是一种
对肠道感染的生理反应,其本身促进Th 17的产生
细胞和炎性细胞因子,并改变免疫系统的基调远离耐受性
争取豁免权通过在没有肠道感染或损伤的情况下研究这一过程,我们可以
将病原体和损伤对炎症反应的贡献从内在的
肠道生态系统的特性促进从致耐受性状态到促炎状态的转换。
了解肠道的内在特性,允许快速产生保护性
反应可以提供新的方法来治疗肠道感染,并提供深入了解
肠道慢性炎症性疾病的发病机制。我们假设当SI间隙
当Th 17细胞被抑制时,其他途径接管驱动Th 17细胞的发育和/或扩增
对饮食、微生物和/或自身抗原具有特异性,这会改变免疫系统的基调,
在肠道感染和/或损伤期间提供增强的保护。为了探索这一假设,
我提出以下具体目标:在目标1中,我们将确定导致Th 17的早期事件
在S1 GAP抑制后的扩增中,在目标2中,我们将定义S1 GAP抑制后的扩增的起源和特异性。
在目标3中,当S1 GAP被抑制时,扩增的Th 17细胞,我们将确定S1 GAP的抑制是否是有效的。
SI GAP在肠道感染模型中具有保护作用,
GAP增强肠道炎症性疾病。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Identification of Gut Bacteria such as Lactobacillus johnsonii that Disseminate to Systemic Tissues of Wild Type and MyD88-/- Mice.
- DOI:10.1080/19490976.2021.2007743
- 发表时间:2022-01
- 期刊:
- 影响因子:12.2
- 作者:Udayan S;Stamou P;Crispie F;Hickey A;Floyd AN;Hsieh CS;Cotter PD;O'Sullivan O;Melgar S;O'Toole PW;Newberry RD;Rossini V;Nally K
- 通讯作者:Nally K
Small Intestinal Goblet Cells Control Humoral Immune Responses and Mobilization During Enteric Infection.
小肠杯状细胞控制肠道感染期间的体液免疫反应和动员。
- DOI:10.1101/2024.01.06.573891
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Kulkarni,DeveshaH;Talati,Khushi;Joyce,ElisabethL;Kousik,Hrishi;Harris,DaliaL;Floyd,AlexandriaN;Vavrinyuk,Vitaly;Barrios,Bibianna;Udayan,Sreeram;McDonald,Keely;John,Vini;Hsieh,Chyi-Song;Newberry,RodneyD
- 通讯作者:Newberry,RodneyD
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{{ truncateString('CHYI S HSIEH', 18)}}的其他基金
B cell-targeted CAR-T treatment of CNS Autoimmunity
B细胞靶向CAR-T治疗中枢神经系统自身免疫
- 批准号:
10514950 - 财政年份:2022
- 资助金额:
$ 44.1万 - 项目类别:
Immune interactions with commensal microbes in early life
生命早期与共生微生物的免疫相互作用
- 批准号:
10567936 - 财政年份:2022
- 资助金额:
$ 44.1万 - 项目类别:
B cell-targeted CAR-T treatment of CNS Autoimmunity
B细胞靶向CAR-T治疗中枢神经系统自身免疫
- 批准号:
10677698 - 财政年份:2022
- 资助金额:
$ 44.1万 - 项目类别:
The Role of Route of Entry by Bacterial Antigens on Colonic T Cell Responses
细菌抗原进入途径对结肠 T 细胞反应的作用
- 批准号:
9912712 - 财政年份:2018
- 资助金额:
$ 44.1万 - 项目类别:
ROLE OF STRESS IN GUT IMMUNE INTERACTIONS WITH COMMENSAL BACTERIA
压力在肠道免疫与共生细菌相互作用中的作用
- 批准号:
10204715 - 财政年份:2018
- 资助金额:
$ 44.1万 - 项目类别:
The Role of Route of Entry by Bacterial Antigens on Colonic T Cell Responses
细菌抗原进入途径对结肠 T 细胞反应的作用
- 批准号:
10396536 - 财政年份:2018
- 资助金额:
$ 44.1万 - 项目类别:
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