Leveraging early-life events to promote tolerance to autoimmunity
利用生命早期事件促进对自身免疫的耐受
基本信息
- 批准号:10853727
- 负责人:
- 金额:$ 5.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAllelesAnatomyAntigen PresentationAntigensAutoantigensAutoimmune DiabetesAutoimmune DiseasesAutoimmunityBacteriaBirthCD4 Positive T LymphocytesCellsChildChildhoodCommunitiesComplementComplexDataDevelopmentDiabetes MellitusDiseaseEnvironmental Risk FactorEventExposure toGeneticGenetic ModelsGerm-FreeGnotobioticGoalsGrowthHLA AntigensHaplotypesHistocompatibility Antigens Class IIHumanImmuneImmune responseImmune systemImmunizationIn VitroInbred NOD MiceIncidenceInsulin-Dependent Diabetes MellitusIntestinesInvestigationKnowledgeLifeMajor Histocompatibility ComplexMapsMediatingMetabolicMicrobeModelingMucous MembraneMusPathway interactionsPeptidesPeripheralPersonsPhylogenetic AnalysisPredispositionPropertyProteinsPublishingRegulatory T-LymphocyteResearchRiskRoleShapesSiteSystemSystems DevelopmentT cell receptor repertoire sequencingT cell responseT-LymphocyteTestingTherapeuticTimeTransgenic MiceTransgenic OrganismsWeaningWorkdiabetes pathogenesisearly life exposureeffective therapygenetic linkagegut microbiomegut microbiotahost microbiotaimmunoregulationin vivoinnovationinsightintestinal homeostasisislet autoimmunitymass spectrometric imagingmembermetabolomicsmicrobialmicrobial communitymicrobial productsmicrobiomemicrobiotamicroorganism antigenmicroorganism interactionmouse modelpreventprotective effectrational designresponserestrainttooltransmission processvalidation studies
项目摘要
PROJECT SUMMARY
Type 1 diabetes (T1D) is an autoimmune disease that affects millions of people worldwide. The incidence of
T1D is rising, especially in young children. Although significant progress has been made to predict who is at risk
for developing T1D, there are no effective therapies to prevent this disease. Both genetic and environmental
factors contribute to the risk of developing T1D. Certain major histocompatibility complex/human leukocyte
antigen (MHC/HLA) class II haplotypes dominantly protect against the development of T1D, and we recently
discovered that protective MHCII molecules shape early-life microbial communities which in turn impact immune
system development to prevent T1D. Modeling microbial protection from T1D in NOD mice may provide critical
insights to support our long-term goal of developing microbiota-based therapies to prevent T1D in humans. Due
to the complexity and high levels of variability of the intestinal microbiome, determining the specific microbial
strains that drive immune system development and function is problematic. The development of gnotobiotic mice
with defined adult microbial communities has been an important advance in the field because they simplify the
complexity and variability of the system and allow for well-controlled, mechanistic studies. However, a gnotobiotic
mouse model to study pediatric disease is lacking. We developed a new gnotobiotic mouse model of the early-
life microbiome which we call Pediatric Community or “PedsCom”. PedsCom is a consortium of 9 bacterial
strains isolated from the intestine of pre-weaning diabetes-protected Eα16/NOD mice. Remarkably, this 9-
microbe community robustly induces regulatory T cells (Tregs) and confers protection from T1D to diabetes-
susceptible NOD mice. We hypothesize that specific PedsCom microbes work in concert to prevent T1D
by providing microbial antigens and metabolites that induce peripheral regulatory T cells (pTregs) during
a critical early life window of immune system development. Aim 1 examines the timing, localization, and
metabolites produced by specific PedsCom members which drive pTreg cell development and prevent
autoimmunity. Aim 2 examines the mechanisms by which pTregs are induced by PedsCom microbes and their
protein antigens and whether pTregs whose TCRs recognize specific microbial antigens mediate protection from
T1D. Successful completion of these aims will provide critical information on which early-life microbes induce
pTregs, and the degree to which microbial antigens and metabolites work together to generate a diabetes-
protective immune system. In addition, PedsCom mice are an innovative tool for investigating early-life host-
microbiota interactions.
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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Michael A Silverman其他文献
Erratum to: A glycine zipper motif mediates the formation of toxic beta-amyloid oligomers in vitro and in vivo
- DOI:
10.1186/1750-1326-9-12 - 发表时间:
2014-03-25 - 期刊:
- 影响因子:17.500
- 作者:
Virginia Fonte;Vishantie Dostal;Christine M Roberts;Patrick Gonzales;Pascale N Lacor;Pauline T Velasco;Jordi Magrane;Natalie Dingwell;Emily Y Fan;Michael A Silverman;Gretchen H Stein;Christopher D Link - 通讯作者:
Christopher D Link
Michael A Silverman的其他文献
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{{ truncateString('Michael A Silverman', 18)}}的其他基金
Leveraging early-life microbes to prevent type 1 diabetes
利用生命早期微生物预防 1 型糖尿病
- 批准号:
10659611 - 财政年份:2023
- 资助金额:
$ 5.51万 - 项目类别:
Leveraging humoral immunity to promote commensal microbial protection from T1D
利用体液免疫促进共生微生物对 T1D 的保护
- 批准号:
10042330 - 财政年份:2020
- 资助金额:
$ 5.51万 - 项目类别:
A Pediatric Microbial Community to Dissect Host-Commensal Interactions in Type 1 Diabetes
儿科微生物群落剖析 1 型糖尿病中宿主共生相互作用
- 批准号:
9979249 - 财政年份:2020
- 资助金额:
$ 5.51万 - 项目类别:
Leveraging humoral immunity to promote commensal microbial protection from T1D
利用体液免疫促进共生微生物对 T1D 的保护
- 批准号:
10196996 - 财政年份:2020
- 资助金额:
$ 5.51万 - 项目类别:
Transfer: Dissecting the interplay of MHC/HLA loci, the microbiota and autoimmune diabetes
转移:剖析 MHC/HLA 位点、微生物群和自身免疫性糖尿病的相互作用
- 批准号:
9413309 - 财政年份:2015
- 资助金额:
$ 5.51万 - 项目类别:
Dissecting the interplay of MHC/HLA loci, the microbiota and autoimmune diabetes
剖析 MHC/HLA 位点、微生物群和自身免疫性糖尿病的相互作用
- 批准号:
8805092 - 财政年份:2015
- 资助金额:
$ 5.51万 - 项目类别:
FUNCTIONAL NEUROANATOMY OF SOCIAL ECONOMIC STRESS
社会经济压力的功能神经解剖学
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7718139 - 财政年份:2008
- 资助金额:
$ 5.51万 - 项目类别:
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