Modulation of dendritic cell function in the pathogenesis of Inflammatory Bowel Diseases
炎症性肠病发病机制中树突状细胞功能的调节
基本信息
- 批准号:9754114
- 负责人:
- 金额:$ 34.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-15 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAdaptive Immune SystemAddressAffectAmericanAntigen PresentationAntigensAutoimmune DiseasesCD8-Positive T-LymphocytesCD8B1 geneCeliac DiseaseCell CompartmentationCell physiologyCellsChronicClinicalColitisComplexCrohn&aposs diseaseDataDendritic CellsDendritic cell activationDevelopmentDioxygenasesDisabled Homolog 2 ProteinDisabled PersonsDiseaseDown-RegulationEnvironmentFOXP3 geneGenetic Predisposition to DiseaseIL2RA geneImmuneImmune ToleranceImmune responseImmunityImmunosuppressive AgentsImpairmentIn VitroIndividualInflammationInflammatoryInflammatory Bowel DiseasesInflammatory ResponseInflammatory disease of the intestineInnate Immune SystemInterleukin-15IntestinesLeadLoeys-Dietz SyndromeMediatingMediator of activation proteinMedicalMolecularMucous MembraneMusMutationPathogenesisPathway interactionsPatientsPhasePhenotypePhosphorylationPhysiologicalPlayPopulationProcessProductionPropertyRecurrent diseaseRefractoryRegulatory T-LymphocyteReportingResearchResidenciesResistanceResistance developmentRoleShapesSignal TransductionSymptomsSystemT cell responseT-LymphocyteTLR3 geneTLR4 geneTestingTherapeuticTissuesTransforming Growth Factor betaUlcerative ColitisWorkautoinflammatorycommensal bacteriacytokineflexibilityfunctional disabilitygastrointestinalimmunoregulationimprovedindoleaminemouse modelnoveloral tolerancereceptorresponsetool
项目摘要
7. Project Summary/Abstract
The development of resistance to immunomodulatory and tolerogenic effects of TGFβ in the immune cells is of
key importance in the pathogenesis of auto-inflammatory disorders, including Inflammatory Bowel Diseases
(IBD). While most effort has been directed towards understanding of such resistance in the cells of the
adaptive immune system, similar phenomenon has not yet been described in the innate immune cells. Mucosal
dendritic cells (DCs) play a crucial role in both immunity and tolerance, and by extension, in the pathogenesis
of autoimmune disorders, including IBD. We provide new evidence to show that DC activation leads to a
development of TGFβ resistance, and identify two putative mediators of this phenomenon – IL15/IL15Rα
complex and DAB2 protein. We developed a mouse model mimicking DC-specific TGFβ resistance
(TGFbR2ΔDC mice) in which we demonstrate severe consequences in form of gastrointestinal auto-
inflammatory disorder. Both CD4+ and CD8+ T cells are required for the pathogenesis of colitis in TGFbR2ΔDC
mice, which is accompanied with altered regulatory T cell compartment (Treg; expansion of CD4+CD25-FoxP3+
Tregs and reduction of CD8+CD103+ Tregs). With the developed mouse models and molecular tools, we will
purse the hypothesis that DC activation by inflammatory and/or infectious insults result in elevated
expression of IL15/IL15Rα complexes and downregulation of Dab2 that lead to TGFβ resistance in
dendritic cells, a phenomenon resulting in impaired Treg development and function and an
establishment of chronic intestinal inflammation. We propose to address this hypothesis in the following
three specific aims: (1) To define the primary subset(s) of intestinal DCs affected with refractory TGFβ
response during intestinal inflammation; (2) To characterize the mechanism responsible for the refractory
response to TGFβ in activated DCs; (3) To define the phenotypic and functional impairment of CD4+ and CD8+
Treg phenotype and function that develops as a consequence of TGFβ resistance in dendritic cells. Our work
will address a physiologically and clinically important, yet unexplored, phenomenon of TGFβ resistance
acquired by activated dendritic cells. It will identify the molecular and cellular mechanisms responsible, and
describe the consequences of such resistance in the context of autoinflammatory disorders.
7.项目总结/摘要
免疫细胞中对TGFβ免疫调节和耐受性作用的抗性的发展是
在自身炎症性疾病(包括炎症性肠道疾病)的发病机制中至关重要
(IBD)。虽然大多数努力都是针对理解细胞中的这种抗性,
在适应性免疫系统中,类似的现象尚未在先天免疫细胞中描述。粘膜
树突状细胞(DCs)在免疫和耐受中起着关键作用,并在发病机制中起着重要作用
自身免疫性疾病包括炎症性肠病我们提供了新的证据表明,DC激活导致
TGFβ抵抗的发展,并确定这种现象的两种假定介质-IL 15/IL 15 R α
复合物和DAB 2蛋白。我们开发了一种模拟DC特异性TGFβ抵抗的小鼠模型,
(TGFbR 2 ΔDC小鼠)中,我们证明了胃肠道自分泌形式的严重后果。
炎症性疾病CD 4+和CD 8 + T细胞在TGFbR 2 ΔDC结肠炎发病中的作用
小鼠,其伴有改变的调节性T细胞区室(Treg; CD 4 + CD 25-FoxP 3+的扩增
T细胞亚群和CD 8 + CD 103 + T细胞亚群的减少)。随着小鼠模型和分子工具的发展,我们将
支持由炎症和/或感染性损伤引起的DC激活导致
IL 15/IL 15 R α复合物的表达和Dab 2的下调导致TGFβ抵抗,
树突状细胞,一种导致Treg发育和功能受损的现象,
慢性肠道炎症的建立。我们建议在下面讨论这个假设
三个具体目标:(1)确定受难治性TGFβ影响的肠道DC的主要亚群
(2)研究肠道炎症反应的机制;(3)研究肠道炎症反应的机制。
(3)确定活化DC中CD 4+和CD 8 + T细胞表型和功能受损情况
Treg表型和功能是树突状细胞中TGFβ抗性的结果。我们的工作
将解决一个生理和临床上重要的,但尚未探索的,TGFβ抵抗现象
通过激活的树突状细胞获得。它将确定负责的分子和细胞机制,
描述了在自身炎症性疾病的背景下这种抵抗的后果。
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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Fayez Khalaf Ghishan其他文献
Fayez Khalaf Ghishan的其他文献
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{{ truncateString('Fayez Khalaf Ghishan', 18)}}的其他基金
PARP1 and PARylation as novel effectors of gut inflammation
PARP1 和 PARylation 作为肠道炎症的新型效应物
- 批准号:
10679646 - 财政年份:2023
- 资助金额:
$ 34.54万 - 项目类别:
Novel Roles of Sodium Hydrogen Exchanger 8 (NHE8) in Mucosal Homeostasis
钠氢交换器 8 (NHE8) 在粘膜稳态中的新作用
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9402244 - 财政年份:2017
- 资助金额:
$ 34.54万 - 项目类别:
Novel Roles of Sodium Hydrogen Exchanger 8 (NHE8) in Mucosal Homeostasis
钠氢交换器 8 (NHE8) 在粘膜稳态中的新作用
- 批准号:
9980395 - 财政年份:2017
- 资助金额:
$ 34.54万 - 项目类别:
Modulation of dendritic cell function in the pathogenesis of Inflammatory Bowel Diseases
炎症性肠病发病机制中树突状细胞功能的调节
- 批准号:
9349503 - 财政年份:2016
- 资助金额:
$ 34.54万 - 项目类别:
Summers in Children's Research for Diverse High School Students
不同高中生的儿童研究暑期活动
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10610857 - 财政年份:2013
- 资助金额:
$ 34.54万 - 项目类别:
Summers in Children's Research for Diverse High School Students
不同高中生的儿童研究暑期活动
- 批准号:
10383164 - 财政年份:2013
- 资助金额:
$ 34.54万 - 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
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8332260 - 财政年份:2006
- 资助金额:
$ 34.54万 - 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
- 批准号:
8913142 - 财政年份:2006
- 资助金额:
$ 34.54万 - 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
- 批准号:
7657335 - 财政年份:2006
- 资助金额:
$ 34.54万 - 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
- 批准号:
7268715 - 财政年份:2006
- 资助金额:
$ 34.54万 - 项目类别:
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