Regulation of C. difficile colitis by host genetic and immune factors
宿主遗传和免疫因素对艰难梭菌结肠炎的调节
基本信息
- 批准号:10683220
- 负责人:
- 金额:$ 40.78万
- 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:2021-09-17 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAntibodiesApoptosisArginineAutomobile DrivingAutophagocytosisBCL2 geneBacteriaBiologicalBiological Response ModifiersBloodBreedingCalibrationCategoriesCellsChemotactic FactorsChemotaxisClinicalClostridium difficileColonConfocal MicroscopyDNA Sequence AlterationDataDevelopmentDiseaseDisease OutcomeEnzyme-Linked Immunosorbent AssayEpithelial CellsExhibitsExposure toFlow CytometryGenesGeneticGlutamineGrantHematopoieticHumanImageImmuneImmune responseImmunoglobulin GImmunohistochemistryImmunologic FactorsIn VitroInduction of ApoptosisInfectionInflammation MediatorsInflammatoryInflammatory ResponseIntegration Host FactorsInterleukin-8B ReceptorIntestinesLabelLeptinLongevityLoxP-flanked alleleMacrophageMigration AssayMigration Inhibitory FactorModelingMusMutationNeutrophiliaNosocomial InfectionsOrganoidsOutcomePathogenesisPathologyPathway interactionsPeptide Signal SequencesPlasmaProductionProteinsPseudomembranous ColitisPublic HealthPublishingRegulationReporterReportingRiskRoleSeveritiesSeverity of illnessShapesSingle Nucleotide PolymorphismSourceStainsTestingTissuesToxinWestern Blottingadverse outcomecomparison controlcytokinedesignexperimental studyimprovedin vivoinduced pluripotent stem cellinhibition of autophagyinsightintestinal epitheliumleptin receptormortalitymutantneutrophilnew therapeutic targetnovelpathogenpharmacologicreceptorreconstitutionrelease factortissue injurytrafficking
项目摘要
Project Summary:
Clostridium difficile is the leading nosocomial infection in the U.S. Host factors are a key predictor of disease
outcomes after C. difficile infection (CDI). We have discovered a key role for leptin receptor (LEPR) pathway and
the pro-inflammatory cytokine Macrophage Inhibitory Factor (MIF) in CDI pathogenesis. Our data reveal that a
common single nucleotide polymorphism (SNP) in the gene for LEPR (Q223R; present in up to 50% of humans)
is associated with exaggerated MIF production after CDI in humans. CDI in mice homozygous for the mutant
SNP (RR) resulted in higher MIF production, more colonic neutrophilia and tissue damage, without effects on
pathogen. We reported that neutralizing MIF using antibody resulted in reduced tissue injury and improved
survival in mice, without effects on C. difficile pathogen. Finally, blocking a key receptor for MIF, CXC chemokine
receptor 2 (CXCR2) also reduced CDI-induced neutrophil accrual in tissue. This proposal is based on these
published results and new preliminary data which indicate that LEPR Q to R change augments Bcl-2 like protein
11 (Bim) expression which controls MIF release by modulating pathways of autophagy/mitophagy/apoptosis.
The overall hypothesis of our studies is that: LEPR Q to R substitution exaggerates CDI-induced, Bim-dependent
MIF release that augments CXCR2-dependent tissue neutrophil accrual and worsens disease severity. To test
this hypothesis, we propose three specific aims. Aim 1 will define the key pathogen-associated drivers of MIF
and the main cellular sources of MIF production in CDI. We will use WT and toxin-deficient C. difficile strains to
determine the role of toxins and non-toxin factors in driving MIF expression. Cellular sources of MIF will be
defined after CDI in WT mice by intracellular staining and immunohistochemistry and their role in CDI will be
tested by using selective MIF deletion in intestinal epithelial cells and in hematopoietic cells. Aim 2 will examine
the mechanism of CDI-induced MIF release. We will determine the role of LEPR Q to R substitution in regulating
Bim expression and subsequent autophagy, mitophagy and apoptosis pathways. Studies will use Bim-reporter
and Bim-deficient mice, and Bim+/+ and Bim-/- human intestinal organoids generated from induced pluripotent
stem cells in both QQ and RR background. Aim 3 will investigate the role of MIF-CXCR2 axis in CDI-induced
tissue neutrophilia in QQ and RR mice. We will compare the effect of MIF on neutrophil trafficking and on their
lifespan. We will utilize neutrophils derived from WT and CXCR2-/- mice in in vitro (migration assays) and in vivo
(after depletion of endogenous neutrophils and reconstitution with labeled neutrophils prior to infection)
experiments. We expect these studies to provide a greater understanding of the role of host genetics in regulating
MIF during CDI pathogenesis. Our studies have the potential to identify new host-based targets that can be used
in the design of novel CDI therapies.
项目总结:
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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Rajat Madan其他文献
Rajat Madan的其他文献
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{{ truncateString('Rajat Madan', 18)}}的其他基金
Regulation of C. difficile colitis by host genetic and immune factors
宿主遗传和免疫因素对艰难梭菌结肠炎的调节
- 批准号:
10362805 - 财政年份:2021
- 资助金额:
$ 40.78万 - 项目类别:
Regulation of C. difficile colitis by host genetic and immune factors
宿主遗传和免疫因素对艰难梭菌结肠炎的调节
- 批准号:
10490905 - 财政年份:2021
- 资助金额:
$ 40.78万 - 项目类别:
Role of a common leptin receptor polymorphism in regulating neutrophil heterogeneity after C. difficile infection
常见瘦素受体多态性在艰难梭菌感染后调节中性粒细胞异质性中的作用
- 批准号:
10266039 - 财政年份:2019
- 资助金额:
$ 40.78万 - 项目类别:
Role of a common leptin receptor polymorphism in regulating neutrophil heterogeneity after C. difficile infection
常见瘦素受体多态性在艰难梭菌感染后调节中性粒细胞异质性中的作用
- 批准号:
9974287 - 财政年份:2019
- 资助金额:
$ 40.78万 - 项目类别:
Role of a common leptin receptor polymorphism in regulating neutrophil heterogeneity after C. difficile infection
常见瘦素受体多态性在艰难梭菌感染后调节中性粒细胞异质性中的作用
- 批准号:
10852810 - 财政年份:2019
- 资助金额:
$ 40.78万 - 项目类别:
Role of leptin in mucosal protection during Clostridium difficile infection
瘦素在艰难梭菌感染期间粘膜保护中的作用
- 批准号:
9113497 - 财政年份:2014
- 资助金额:
$ 40.78万 - 项目类别:
Role of leptin in mucosal protection during Clostridium difficile infection
瘦素在艰难梭菌感染期间粘膜保护中的作用
- 批准号:
8767529 - 财政年份:2014
- 资助金额:
$ 40.78万 - 项目类别:
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