Gene-environment interactions in necrotizing enterocolitis: impact of SIGIRR mutation and gut microbiota on intestinal TLR hyperactivity
坏死性小肠结肠炎的基因-环境相互作用:SIGIRR 突变和肠道微生物群对肠道 TLR 过度活跃的影响
基本信息
- 批准号:10670362
- 负责人:
- 金额:$ 16.24万
- 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:2020-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AntibioticsApoptosisAwardBioinformaticsBiologyCRISPR/Cas technologyCellular biologyChildCitiesComplexDataDevelopmentEnvironmentEtiologyExhibitsFamilyFosteringFundingGenesGeneticGenetic ModelsGenetic Predisposition to DiseaseGenetic studyGoalsHomeostasisHumanHyperactivityImmuneImmunoglobulinsImmunologic ReceptorsIncidenceInfantInflammationInflammatory Bowel DiseasesInjuryInterleukin-1IntestinesKansasKnock-in MouseKnowledgeLaboratoriesMeasuresMedicineMentorsMentorshipMolecular BiologyMusMutationNatureNecrotizing EnterocolitisNeonatalOutcomePathogenesisPathologicPediatricsPhenotypePhysiciansPositioning AttributePre-Clinical ModelPredispositionPremature InfantPreventionProbioticsReceptor ActivationReceptor SignalingResearchResearch EthicsResearch PersonnelRoleScientistTestingTherapeuticTimeToll-like receptorsTrainingTransgenic MiceUnited States National Institutes of Healthbacterial communitycareerdisorder riskdriving forcedysbiosisexperiencefecal transplantationgene environment interactiongut homeostasisgut inflammationgut microbiomegut microbiotahigh riskimproved outcomeindividualized medicineinsightmicrobialmicrobial based therapymicrobiomemicrobiome alterationmicrobiome researchmicrobiome sequencingmicrobiome signaturemicrobiota profilesmouse modelnovelprofessorprogramsreceptorreverse geneticsskillssuccesstherapeutic evaluationtranslational impact
项目摘要
PROJECT SUMMARY/ABSTRACT
This NIH K08 proposal describes a five-year training and research plan for the candidate, a physician-scientist
with a long-term goal of becoming an independent investigator in the field of neonatal medicine. Toward this
end, the proposed research is directed at defining the pathogenesis of necrotizing enterocolitis (NEC) – a
devastating inflammatory bowel disease of preterm infants that is characterized mainly by the excessive
activation of the Toll-Like Receptor (TLR) family of innate immune receptors. Inherent genetic susceptibility
and the intestinal microbiota environment are two factors strongly implicated in NEC pathogenesis. These
factors have primarily been evaluated in isolation from each other – an important limitation that does not
replicate the complex nature of NEC.
Recently, our laboratory generated novel transgenic mice that recapitulate a mutation discovered in infants
with NEC. This mutation is a stop mutation of Single-Immunoglobulin Interleukin-1 Related Receptor (SIGIRR),
a gene that normally functions to inhibit gut TLR signaling. The generated SIGIRR transgenic mice (SIGIRRTG)
exhibit a phenotype of increased gut TLR activity at baseline conditions. In this study, the candidate proposes
to use this novel mouse line as a genetic model of NEC to determine the interaction between genetics and the
gut microbiome as it relates to gut TLR activity. Aim #1 will determine the impact of SIGIRR mutation on gut
microbiota signatures. Aim #2 will determine whether increased intestinal TLR activity in SIGIRRTG mice is
driven by gut microbiota. Aim #3 will determine the effect of gut microbiome alteration in reversing genetic
predisposition of SIGIRRTG mice towards intestinal inflammation. Completion of these aims will provide novel
insights into how genes and the gut microbiome interact to influence TLR homeostasis in the developing gut.
New knowledge gained will represent a significant advancement in understanding the complex pathogenesis of
NEC that can be used to inform the development of personalized, microbiome-based therapies for NEC.
The candidate is firmly committed to a career in basic and translational NEC research and is strongly
supported in his career and research goals by his mentors and his department at Children’s Mercy Kansas
City. He currently holds a position as an Assistant Professor of Pediatrics with 75% protected time for
research, independent laboratory and office space, and start-up funding. The current proposal includes a
comprehensive mentorship and didactic plan to advance the candidate’s skills and knowledge in TLR biology,
microbial pathogenesis, cell and molecular biology, microbiome sequencing, bioinformatics, and research
ethics. Completion of this comprehensive training plan will provide the candidate with the skills and experience
necessary to develop an independent research program and obtain R01 funding.
项目总结/摘要
这份NIH K 08提案描述了一个为期五年的培训和研究计划,为候选人,一个医生,科学家
长期目标是成为新生儿医学领域的独立研究者。朝着这个
最后,本研究旨在明确坏死性小肠结肠炎(NEC)的发病机制,
早产儿的毁灭性炎症性肠病,其主要特征是
先天免疫受体的Toll样受体(TLR)家族的激活。遗传易感性
和肠道微生物群环境是与NEC发病机制密切相关的两个因素。这些
这些因素主要是在相互孤立的情况下进行评估的,这是一个重要的限制,
复制NEC的复杂性。
最近,我们的实验室培育了一种新型转基因小鼠,
关于NEC该突变是单免疫球蛋白白细胞介素-1相关受体(SIGIRR)的终止突变,
一种通常抑制肠道TLR信号的基因。产生的SIGIRR转基因小鼠(SIGIRRTG)
在基线条件下表现出肠TLR活性增加的表型。在这项研究中,候选人提出
使用这种新的小鼠品系作为NEC的遗传模型,以确定遗传学和基因之间的相互作用。
肠道微生物组,因为它与肠道TLR活性有关。目标#1将确定SIGIRR突变对肠道的影响
微生物群特征目的#2将确定SIGIRRTG小鼠中肠TLR活性的增加是否是
由肠道微生物群驱动目的#3将确定肠道微生物组改变在逆转遗传性疾病中的作用。
SIGIRRTG小鼠对肠道炎症的易感性。这些目标的实现将提供新的
深入了解基因和肠道微生物组如何相互作用,以影响发育中肠道的TLR稳态。
获得的新知识将代表着在理解复杂的发病机制方面的重大进展,
NEC,可用于为NEC的个性化,基于微生物组的治疗提供信息。
候选人坚定地致力于基础和转化NEC研究的职业生涯,
在他的职业生涯和研究目标的支持下,他的导师和他的部门在儿童慈善堪萨斯
市他目前担任儿科助理教授,有75%的时间受到保护,
研究、独立的实验室和办公空间以及启动资金。目前的提案包括一个
全面的指导和教学计划,以提高候选人在TLR生物学方面的技能和知识,
微生物发病机理,细胞和分子生物学,微生物组测序,生物信息学和研究
伦理完成这一全面的培训计划将提供候选人的技能和经验
需要开发一个独立的研究计划,并获得R 01资金。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Racial Disparities in Necrotizing Enterocolitis.
- DOI:10.3389/fped.2021.633088
- 发表时间:2021
- 期刊:
- 影响因子:2.6
- 作者:Cuna A;Sampath V;Khashu M
- 通讯作者:Khashu M
Association of time of first corticosteroid treatment with bronchopulmonary dysplasia in preterm infants.
- DOI:10.1002/ppul.25610
- 发表时间:2021-10
- 期刊:
- 影响因子:3.1
- 作者:Cuna A;Lagatta JM;Savani RC;Vyas-Read S;Engle WA;Rose RS;DiGeronimo R;Logan JW;Mikhael M;Natarajan G;Truog WE;Kielt M;Murthy K;Zaniletti I;Lewis TR;Children's Hospitals Neonatal Consortium (CHNC) Severe BPD Focus Group
- 通讯作者:Children's Hospitals Neonatal Consortium (CHNC) Severe BPD Focus Group
Effectiveness and safety of repeat dexamethasone for bronchopulmonary dysplasia.
- DOI:10.1038/s41372-021-01125-3
- 发表时间:2021-08
- 期刊:
- 影响因子:0
- 作者:Cuna A;Quiqley A;Varghese K;Ciccolari-Micaldi G;Oliveros C;Cheng AL;Norberg M;Truog WE
- 通讯作者:Truog WE
The Detrimental Effects of Peripartum Antibiotics on Gut Proliferation and Formula Feeding Injury in Neonatal Mice Are Alleviated with Lactobacillus rhamnosus GG.
- DOI:10.3390/microorganisms11061482
- 发表时间:2023-06-01
- 期刊:
- 影响因子:4.5
- 作者:
- 通讯作者:
Early antibiotics and risk for necrotizing enterocolitis in premature infants: A narrative review.
- DOI:10.3389/fped.2023.1112812
- 发表时间:2023
- 期刊:
- 影响因子:2.6
- 作者:
- 通讯作者:
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Alain Cuna其他文献
Alain Cuna的其他文献
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{{ truncateString('Alain Cuna', 18)}}的其他基金
Gene-environment interactions in necrotizing enterocolitis: impact of SIGIRR mutation and gut microbiota on intestinal TLR hyperactivity
坏死性小肠结肠炎的基因-环境相互作用:SIGIRR 突变和肠道微生物群对肠道 TLR 过度活跃的影响
- 批准号:
10452765 - 财政年份:2020
- 资助金额:
$ 16.24万 - 项目类别:
Gene-environment interactions in necrotizing enterocolitis: impact of SIGIRR mutation and gut microbiota on intestinal TLR hyperactivity
坏死性小肠结肠炎的基因-环境相互作用:SIGIRR 突变和肠道微生物群对肠道 TLR 过度活跃的影响
- 批准号:
10212387 - 财政年份:2020
- 资助金额:
$ 16.24万 - 项目类别:
Gene-environment interactions in necrotizing enterocolitis: impact of SIGIRR mutation and gut microbiota on intestinal TLR hyperactivity
坏死性小肠结肠炎的基因-环境相互作用:SIGIRR 突变和肠道微生物群对肠道 TLR 过度活跃的影响
- 批准号:
10034831 - 财政年份:2020
- 资助金额:
$ 16.24万 - 项目类别:
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