Uncovering the role of LRH-1 in enteroendocrine cell development and ‘gut-brain’ communication
Uncovering the role of LRH-1 in enteroendocrine cell development and ‘gut-brain’ communication
批准号:
9920708
负责人:
James Bayrer
金额:
$12.09万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-04-25 至 2021-03-31
关键词:
AcuteAffectAnatomyApoptosisBiologyBody Surface AreaCell CountCell Differentiation processCell LineageCell SurvivalCellsChIP-seqChemicalsCommunicationComplementCoupledDNA BindingDataDevelopmentDigestionEmbryonic DevelopmentEnteroendocrine CellEpithelialEpithelial CellsEpithelial PhysiologyEpitheliumEsthesiaEvaluationFecesGastrointestinal TransitGastrointestinal tract structureGeneticGenetic TranscriptionGoalsHistologicHomeostasisIn Situ HybridizationIntestinal MotilityIntestinal SecretionsIntestinesInvestigationKnock-outLGR5 geneLabelLeadLiquid substanceMaintenanceMeasuresMechanicsMetabolicMetabolismModelingMolecularMucous MembraneMultipotent Stem CellsNR5A2 geneNerve FibersNeuronsNotch Signaling PathwayNuclearNuclear ReceptorsOrganoidsPathogenicityPhenotypePlayPopulationProductionPropertyProxyReporterResearchRoleSecretory CellSensorySignal TransductionStimulusSynapsesSystemTechnologyTimeVisceralWaterWorkcell dedifferentiationcell motilitycell typecolorectal distensioncrypt celldata submissiondesignexperimental studygastrointestinal epitheliumgut-brain axisintestinal cryptintestinal epitheliumlive cell imagingmouse modelnerve supplyneurotransmissionnew technologynotch proteinpluripotencyprogramsrapid growthresponsesingle cell sequencingsingle-cell RNA sequencingstem cell homeostasisstem cellstime use
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
Background:
The intestinal epithelium represents one of the largest exposed surface areas of the body and must perform
multiple functions related to digestion, infectious surveillance, and metabolism. Helping to coordinate these
activities are enteroendocrine cells (EECs), specialized intestinal epithelial cells expressing cellular machinery
for chemical and mechanical sensing and for host communication via the ‘Gut-Brain Axis.’ Liver receptor
homolog-1 (LRH-1, NR5A2) is a nuclear receptor expressed in the intestinal epithelium. We have shown LRH-
1 is critical for the production of these unique cells and that loss of LRH-1 leads to a remarkable visceral
hyposensitivity. In this application, we propose to elucidate both the mechanism(s) by which LRH-1 promotes
the differentiation of EECs and the functional consequences of their loss on gut-brain communication.
Approach:
We will use a combination of genetic mouse models and intestinal organoid technology to investigate LRH-1-
dependent EEC differentiation. Using a single cell sequencing approach, we will identify EEC progenitor
population shifts following loss of LRH-1. Leveraging an EEC progenitor fluorescent marker, we will observe in
real time the effects of LRH-1 knockout on EEC cell differentiation and to delineate the LRH-1 DNA binding
targets. Our molecular studies will be complemented by an evaluation of the functional consequences of LRH-
1-dependent EEC loss. Finally, use of detailed anatomic studies in our acute LRH-1 knockout models will
enable us to explore the effects of rapid EEC disruption on mucosal nerve fibers, a key component of the gut-
brain axis.
Goals:
This proposal is designed to expand upon a key finding uncovered during my K08 investigation and to fully
establish my independent research program. These experiments will provide important data for submission of
a successful R01 proposal built at the extraordinary confluence of intestinal epithelial physiology, nuclear
receptor biology, and neuronal signaling.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Decoding LRH-1 Activity in Gut Regeneration and Differentiation
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批准号:10427197
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项目类别:
-
资助金额:$52.53万
-
财政年份:2021
-
负责人:James Bayrer
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依托单位:
Decoding LRH-1 Activity in Gut Regeneration and Differentiation
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批准号:10726639
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项目类别:
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资助金额:$12.16万
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财政年份:2021
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负责人:James Bayrer
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依托单位:
Resubmission of Diversity Supplement
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批准号:10579764
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项目类别:
-
资助金额:$12.16万
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财政年份:2021
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负责人:James Bayrer
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依托单位:
Decoding LRH-1 Activity in Gut Regeneration and Differentiation
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批准号:10184708
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项目类别:
-
资助金额:$52.53万
-
财政年份:2021
-
负责人:James Bayrer
-
依托单位:
Decoding LRH-1 Activity in Gut Regeneration and Differentiation
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批准号:10613992
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项目类别:
-
资助金额:$52.53万
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财政年份:2021
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负责人:James Bayrer
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依托单位:
Targeting Intestinal Epithelium to Promote Healing in Inflammatory Bowel Disease
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批准号:9517035
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项目类别:
-
资助金额:$16.94万
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财政年份:2016
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负责人:James Bayrer
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依托单位:
Targeting Intestinal Epithelium to Promote Healing in Inflammatory Bowel Disease
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批准号:9180524
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项目类别:
-
资助金额:$15.86万
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财政年份:2016
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负责人:James Bayrer
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依托单位:
LRH-1: Structure-based Approach to Drug Design for Gastrointestinal Tumors
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批准号:8314808
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项目类别:
-
资助金额:$5.94万
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财政年份:2012
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负责人:James Bayrer
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依托单位:
LRH-1: Structure-based Approach to Drug Design for Gastrointestinal Tumors
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批准号:8460183
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项目类别:
-
资助金额:$1.75万
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财政年份:2012
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负责人:James Bayrer
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依托单位:
海外基金