Mechanisms underlying regulation of intestinal epithelial homeostasis in sepsis
脓毒症肠上皮稳态调节的机制
基本信息
- 批准号:10757097
- 负责人:
- 金额:$ 61.67万
- 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:2020-02-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AbbreviationsAchievementAffectAmericanAnimal ModelAttenuatedBiological AssayBone Morphogenetic ProteinsCell ProliferationCell SeparationCellsCellular biologyColumnar CellColumnar EpitheliumDataDeoxyuridineDevelopmentEpithelial Cell ProliferationEpithelial CellsEquilibriumEventFlow CytometryFluorescent in Situ HybridizationFunctional disorderGenetic EngineeringGoalsGut MucosaH19 geneHomeostasisHumanIFITM1 geneImmune System DiseasesImmune systemImpairmentIn VitroInfectionInflammationInflammatoryInhibition of Cell ProliferationInterferon Type IIInterleukin-6Intestinal MucosaIntestinesKnockout MiceKnowledgeLGR5 geneLabelLifeLymphoidMalnutritionMediatingMethodsMolecularMolecular BiologyMolecular TargetMolecular and Cellular BiologyMultiple Organ FailureNatural regenerationOperative Surgical ProceduresOrganOrganoidsPathogenesisPatient-Focused OutcomesPatientsPhysiologicalPlayProcessProliferatingProteinsRNA BindingRegulationResearchRoleSepsisSignal TransductionSpecimenTP53 geneTechniquesTechnologyTestingTraumaTraumatic injuryUntranslated RNAUp-RegulationVillusWNT Signaling PathwayWorkbasececal ligation punctureclinically relevantcytokinecytokine release syndromedysbiosisepithelium regenerationgastrointestinal epitheliumgut homeostasisimprovedin vivointerleukin-22intestinal cryptintestinal epitheliumintestinal homeostasismicrobiomemonocytemouse geneticsmouse modelmultidisciplinarynew therapeutic targetnovelnovel strategiesnovel therapeutic interventionnovel therapeuticspolymicrobial sepsispreservationresponserestorationself-renewalsepticseptic patientssevere burnsstem cell proliferationstem cellssystemic inflammatory response
项目摘要
Sepsis and severe surgical conditions cause profound decrease in epithelial cell proliferation in the intestinal
crypts. This pathophysiological response disrupts intestinal epithelial homeostasis, which is thought to contribute
to the pathogenesis of sepsis-induced immune dysfunction and multiple organ failure. Evidence shows that
sepsis is associated with increased levels of interferon γ (IFNγ), a proinflammatory cytokine known to inhibit
intestinal epithelial cell (IEC) proliferation in vitro. In preliminary studies, we found that IFNγ plays an important
role in disruption of crypt IEC proliferation in sepsis. The proliferative cells in the intestinal crypts are composed
of Lgr5-expressing crypt base columnar cells (Lgr5+-CBCs, a group of intestinal stem cells [ISCs]) and transit
amplifying cells (TACs). However, the mechanism by which sepsis-activated IFNγ signal affects proliferation of
these cells has not been rigorously studied. Furthermore, little is known about how to sustain proliferation of
Lgr5+-CBCs and TACs to maintain homeostasis in sepsis. Recently, we found that sepsis is associated with de
novo expression of a long noncoding RNA (lncRNA) molecule, H19, in Lgr5+-CBCs and TACs in the intestinal
crypts. Remarkably, we discovered that H19 lncRNA plays a critical role in attenuating sepsis-induced reduction
of crypt IEC proliferation and promoting intestinal epithelial regeneration. Mechanistically, H19 lncRNA binds to
molecules that inhibit cell proliferation and attenuates their activity. Collectively, these data suggest that IFNγ
signaling and H19 lncRNA play opposing roles in the regulation of Lgr5+-CBC and TAC proliferation in sepsis. In
this project, we will test the hypothesis that sepsis-induced inflammation activates de novo expression of H19
lncRNA, which in turn antagonizes the deleterious effect of the IFNγ signal axis, thereby releasing inhibition of
Lgr5+-CBC and TAC proliferation and rescuing homeostasis of the intestinal mucosa. To achieve this goal, we
will execute three complementary aims: (1) We will examine whether and how septic inflammation dysregulates
proliferation of Lgr5+-CBCs and TACs by focusing on the role of IFNγ signaling. We will precisely study the
harmful effect of sepsis on proliferation of Lgr5+-CBCs and TACs in vivo utilizing a clinically relevant mouse
model of polymicrobial sepsis, a novel method that combines 5-ethynyl-2'-deoxyuridine labeling with multi-probe
fluorescence in situ hybridization assay, and flow cytometry and cell sorting technology. Furthermore, we will
delineate how IFNγ signaling leads to inhibition of Lgr5+-CBC and TAC proliferation in sepsis. (2) We will
investigate the molecular mechanisms by which de novo expressed H19 lncRNA antagonizes the inhibitory
effect of sepsis on Lgr5+-CBC and TAC proliferation, taking a multidisciplinary in vivo and in vitro approach that
incorporates cell biology, organoid culture, molecular biology, and mouse genetic engineering techniques. (3)
We will study how septic inflammation induces de novo expression of H19 lncRNA in IECs. Successful
achievement of these aims will fill gaps in knowledge about the regulation of intestinal epithelial renewal in sepsis
and ultimately lead to development of new therapies.
脓毒症和严重的手术条件导致肠道上皮细胞增殖严重减少
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
MFG-E8 Plays an Important Role in Attenuating Cerulein-Induced Acute Pancreatitis in Mice.
- DOI:10.3390/cells10040728
- 发表时间:2021-03-25
- 期刊:
- 影响因子:6
- 作者:Bu HF;Subramanian S;Geng H;Wang X;Liu F;Chou PM;Du C;De Plaen IG;Tan XD
- 通讯作者:Tan XD
Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting.
- DOI:10.1080/19490976.2023.2267180
- 发表时间:2023-12
- 期刊:
- 影响因子:12.2
- 作者:
- 通讯作者:
SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells.
- DOI:10.3389/fimmu.2021.679482
- 发表时间:2021
- 期刊:
- 影响因子:7.3
- 作者:Geng H;Subramanian S;Wu L;Bu HF;Wang X;Du C;De Plaen IG;Tan XD
- 通讯作者:Tan XD
Novel Role of Ghrelin Receptor in Gut Dysbiosis and Experimental Colitis in Aging.
- DOI:10.3390/ijms23042219
- 发表时间:2022-02-17
- 期刊:
- 影响因子:5.6
- 作者:Noh JY;Wu CS;DeLuca JAA;Devaraj S;Jayaraman A;Alaniz RC;Tan XD;Allred CD;Sun Y
- 通讯作者:Sun Y
Severe gut mucosal injury induces profound systemic inflammation and spleen-associated lymphoid organ response.
- DOI:10.3389/fimmu.2023.1340442
- 发表时间:2023
- 期刊:
- 影响因子:7.3
- 作者:
- 通讯作者:
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Xiao-Di Tan其他文献
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{{ truncateString('Xiao-Di Tan', 18)}}的其他基金
Milk fat globule-EGF factor 8 and hepatocyte apoptosis-induced liver wound healing response
乳脂肪球-EGF因子8与肝细胞凋亡诱导的肝脏创面愈合反应
- 批准号:
10585802 - 财政年份:2023
- 资助金额:
$ 61.67万 - 项目类别:
Insights into a multi-hit process in the development of necrotizing enterocolitis
深入了解坏死性小肠结肠炎发展中的多重打击过程
- 批准号:
10763712 - 财政年份:2023
- 资助金额:
$ 61.67万 - 项目类别:
Insights into a multi-hit process in the development of necrotizing enterocolitis
深入了解坏死性小肠结肠炎发展中的多重打击过程
- 批准号:
10443445 - 财政年份:2022
- 资助金额:
$ 61.67万 - 项目类别:
Mechanisms underlying regulation of intestinal epithelial homeostasis in sepsis
脓毒症肠上皮稳态调节的机制
- 批准号:
9901333 - 财政年份:2020
- 资助金额:
$ 61.67万 - 项目类别:
Mechanisms underlying regulation of intestinal epithelial homeostasis in sepsis
脓毒症肠上皮稳态调节的机制
- 批准号:
10337285 - 财政年份:2020
- 资助金额:
$ 61.67万 - 项目类别:
Pathogenesis of sepsis-induced dysfunction of innate immunity
脓毒症引起的先天免疫功能障碍的发病机制
- 批准号:
9898295 - 财政年份:2018
- 资助金额:
$ 61.67万 - 项目类别:
Pathogenesis of sepsis-induced dysfunction of innate immunity
脓毒症引起的先天免疫功能障碍的发病机制
- 批准号:
10158422 - 财政年份:2018
- 资助金额:
$ 61.67万 - 项目类别:
Pathogenesis of sepsis-induced dysfunction of innate immunity
脓毒症引起的先天免疫功能障碍的发病机制
- 批准号:
10609788 - 财政年份:2018
- 资助金额:
$ 61.67万 - 项目类别:
Mechanisms of trauma and hemorrhage-induced impairment of innate immunity
创伤和出血引起的先天免疫受损的机制
- 批准号:
8660227 - 财政年份:2013
- 资助金额:
$ 61.67万 - 项目类别:
Mechanisms of trauma and hemorrhage-induced impairment of innate immunity
创伤和出血引起的先天免疫受损的机制
- 批准号:
8803318 - 财政年份:2013
- 资助金额:
$ 61.67万 - 项目类别:
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