Bacterial Stress Responses to Intestinal Inflammation
肠道炎症的细菌应激反应
基本信息
- 批准号:8665916
- 负责人:
- 金额:$ 15.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-05-01 至 2015-04-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAntigensAreaAttenuatedBacteriaBacterial AntigensBacterial GenesBacteriologyBiologicalBiological AssayBiological ModelsBiologyCellsChronicColitisComplementCrohn&aposs diseaseDataDevelopmentDiseaseEnterobacteriaceaeEnvironmentEscherichia coliFundingFutureGene Expression ProfileGenerationsGenesGentamicinsGnotobioticGoalsHeat Stress DisordersHeat shock proteinsImmuneImmune responseImmune systemImmunologyIn VitroIndividualInflammationInflammatoryInflammatory Bowel DiseasesInflammatory disease of the intestineInstitutionInterleukin-10Intestinal MucosaIntestinesInvestigationKnowledgeLeadLearningLinkManuscriptsMeasuresMediatingMentorsMicrobial GeneticsMicrobiologyModelingMolecularMorbidity - disease rateMusOutcomePathogenesisPathway interactionsPhagocytosisPhagolysosomeProductionPropertyProteinsPublishingReactive Oxygen SpeciesRelapseReporterResearchResearch PersonnelResistanceResource SharingResourcesRodentRoleSplenocyteT-LymphocyteTechniquesTestingTherapeuticTimeTime StudyUlcerative ColitisUniversitiesUp-RegulationVirulenceWild Type Mousebiological adaptation to stresscell mediated immune responsecommensal microbescytokinedesigngastrointestinalinhibitor/antagonistinnovationinterestmacrophagemicrobialmicroorganism interactionnovelnovel diagnosticsoxidative damageresponseuptake
项目摘要
DESCRIPTION (provided by applicant): Crohn's disease and ulcerative colitis, collectively known as inflammatory bowel diseases (IBD), are caused in part by overly-aggressive, T cell-mediated immune responses to bacterial products in genetically susceptible hosts. Isolates of Escherichia coli (E. coli) have been associated with Crohn's disease and bacterial components, including stress-response proteins, promote intestinal inflammation by stimulating innate and adaptive host immune systems. While the immune response to bacterial products has been extensively studied, little is known about the subsequent effects of host inflammation on bacterial properties. Selective colonization with a commensal murine strain of E. coli (NC101) causes colitis in IL-10-deficient (IL-10-/-), but not wild-type (wt), mice. Intestinal inflammation triggers NC101 to upregulate the bacterial stress-response gene ibpB. IbpB is a small heat shock protein that helps bacteria tolerate heat stress and high levels of reactive oxygen species (ROS) as is found in the inflamed intestine and macrophage phagolysosomes. HYPOTHESIS: The host inflammatory milieu upregulates bacterial ibpB, which in turn allows bacteria to adapt to the environment and perpetuate inflammation by increasing their survival and virulence. SPECIFIC AIMS: 1) Identify mechanisms by which the host inflammatory milieu stimulates E. coli to upregulate ibpB in vitro. We will study the roles of intracellular and secreted factors in upregulating E. coli ibpB using ibpB-eGFP reporter bacteria and inhibitors of ROS and cytokine production. 2) Ascertain the effects of E. coli ibpB expression on host inflammatory pathways in vitro. We will determine mechanisms by which E. coli IbpB inhibits uptake by macrophages and promotes intracellular survival using genetically altered NC101 and inhibitors of phagocytosis and ROS generation in gentamicin protection assays. 3) Examine the biological relevance of E. coli IbpB in the initiation and perpetuation of chronic experimental colitis in E. coli monoassociated IL-10-/- mice. We will measure histological inflammation, bacterial distribution, innate and adaptive immune responses in wt and IL-10-/- mice monoassociated with NC101 or ibpB-deficient NC101. CAREER DEVELOPMENT: Long-term goals are to lead a research team at an academic institution to: 1) contribute new knowledge to the field of host-microbial interactions, and 2) develop novel diagnostic strategies and therapies for IBD. Short-term goals are to: 1) learn new techniques to complete the proposed and future studies, 2) interact regularly with an exceptional mentoring team, 3) participate in didactic courses and research seminars in microbial genetics and pathogenesis, and 4) differentiate myself from my mentor by publishing manuscripts and submitting applications for independent funding in the area of bacterial stress responses. ENVIRONMENT: The National Gnotobiotic Rodent Resource Center, the Center for Gastrointestinal Biology and Disease, local experts in mucosal immunology and bacteriology, university start-up funds, and an institutional commitment to protect research time will facilitate attainment of these goals.
描述(由申请人提供):克罗恩病和溃疡性结肠炎,统称为炎症性肠病(IBD),部分由遗传易感宿主对细菌产物的过度攻击性T细胞介导的免疫应答引起。分离的大肠杆菌(E.大肠杆菌)与克罗恩病和细菌成分,包括应激反应蛋白,通过刺激先天和适应性宿主免疫系统促进肠道炎症。虽然对细菌产物的免疫反应已被广泛研究,但对宿主炎症对细菌特性的后续影响知之甚少。选择性定殖与E.大肠杆菌(NC 101)在IL-10缺陷型(IL-10-/-)小鼠中引起结肠炎,但在野生型(wt)小鼠中不引起结肠炎。肠道炎症触发NC 101上调细菌应激反应基因ibpB。IbpB是一种小的热休克蛋白,有助于细菌耐受热应激和高水平的活性氧(ROS),如在发炎的肠道和巨噬细胞吞噬溶酶体中发现的。假设:宿主炎症环境上调细菌ibpB,这反过来又允许细菌适应环境并通过增加其存活率和毒力来使炎症永久化。具体目的:1)确定宿主炎症环境刺激E。coli中诱导ibpB表达。我们将研究细胞内和分泌因子在上调E.使用ibpB-eGFP报告细菌和ROS和细胞因子产生的抑制剂,2)确定E. coli ibpB表达对宿主炎症通路的影响。我们将确定的机制,E。在庆大霉素保护试验中,使用遗传改变的NC 101和吞噬作用和ROS产生的抑制剂,coli IbpB抑制巨噬细胞的摄取并促进细胞内存活。3)检测E. coli IbpB在慢性实验性结肠炎的发生和延续中的作用。coli单相关IL-10-/-小鼠。我们将测量与NC 101或ibpB缺陷型NC 101单相关的野生型和IL-10-/-小鼠中的组织学炎症、细菌分布、先天性和适应性免疫应答。职业发展:长期目标是领导学术机构的研究团队:1)为宿主-微生物相互作用领域贡献新知识,2)开发IBD的新诊断策略和疗法。短期目标是:1)学习新技术,以完成拟议的和未来的研究,2)与一个特殊的指导团队定期互动,3)参加微生物遗传学和发病机理的教学课程和研究研讨会,和4)通过发表手稿和提交申请,使自己与我的导师在细菌应激反应领域的独立资金区分开来。环境:国家非生物啮齿类动物资源中心、胃肠生物学和疾病中心、当地粘膜免疫学和细菌学专家、大学启动资金以及保护研究时间的机构承诺将有助于实现这些目标。
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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Jonathan James Hansen其他文献
Jonathan James Hansen的其他文献
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{{ truncateString('Jonathan James Hansen', 18)}}的其他基金
Anti-inflammatory effects of colitis-induced changes in commensal gut microbes
结肠炎引起的肠道共生微生物变化的抗炎作用
- 批准号:
8567015 - 财政年份:2013
- 资助金额:
$ 15.33万 - 项目类别:
Anti-inflammatory effects of colitis-induced changes in commensal gut microbes
结肠炎引起的肠道共生微生物变化的抗炎作用
- 批准号:
8676790 - 财政年份:2013
- 资助金额:
$ 15.33万 - 项目类别:
Bacterial Stress Responses to Intestinal Inflammation
肠道炎症的细菌应激反应
- 批准号:
7872364 - 财政年份:2010
- 资助金额:
$ 15.33万 - 项目类别:
Bacterial Stress Responses to Intestinal Inflammation
肠道炎症的细菌应激反应
- 批准号:
8055878 - 财政年份:2010
- 资助金额:
$ 15.33万 - 项目类别:
Bacterial Stress Responses to Intestinal Inflammation
肠道炎症的细菌应激反应
- 批准号:
8261122 - 财政年份:2010
- 资助金额:
$ 15.33万 - 项目类别:
Bacterial Stress Responses to Intestinal Inflammation
肠道炎症的细菌应激反应
- 批准号:
8458959 - 财政年份:2010
- 资助金额:
$ 15.33万 - 项目类别:
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