Maternal Obesity and Pediatric NAFLD: Fetal Origins and Long-term outcomes in Non Human Primates
母亲肥胖和儿童 NAFLD:非人类灵长类动物的胎儿起源和长期结果
基本信息
- 批准号:10375910
- 负责人:
- 金额:$ 60.21万
- 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:2021-09-30 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3 year oldATAC-seqAdolescentAdultAffectAgeAnimalsAnti-Inflammatory AgentsBile AcidsBindingBirthBone MarrowCellsChildChildhoodClinicalClipCollagenConsumptionCritical PathwaysDataDepositionDevelopmentDietDown-RegulationEmbryoEpigenetic ProcessEthnic OriginFatty acid glycerol estersFetal DiseasesFetal LiverFetusFibrosisGene ExpressionGenetic TranscriptionGlycolysisGoalsHNF4A geneHematopoietic stem cellsHepaticHepatic Stellate CellHepatocyteHumanImmuneImmunoprecipitationImpairmentIn VitroInfantInflammationInflammatoryInflammatory ResponseInjuryInterleukin-4LifeLiverLiver FibrosisLiver diseasesLongevityLongitudinal StudiesMicroRNAsModelingModificationMolecularObesityOutcomeOverweightPathogenesisPathway interactionsPatientsPhenotypePhysiologicalPopulationPortal triadPredispositionPrevalenceProductionRaceRiskRisk FactorsRoleSignal TransductionSignaling ProteinSiteSocioeconomic StatusTestingToddlerWeaningYolk SacYouthbile acid metabolismcell injurycrosslinkcytokineemerging adultepigenomefetalhealingin uterojuvenile animalliver injuryliver metabolismmacrophagematernal obesitymonocytemother nutritionnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnonhuman primatenovelobese mothersoffspringpediatric non-alcoholic fatty liver diseasepostnatalprogramsrecruitresponsesingle-cell RNA sequencingstellate celltranscriptome sequencingwestern diet
项目摘要
PROJECT SUMMARY
The prevalence of maternal overweight and obesity continues to increase in the U.S. and spans the
spectrum of age, race and ethnicity, and socioeconomic status. Alarmingly, 1 in 10 infants and toddlers are
obese, and 1 in 5 youth are both obese and at-risk for pediatric Non-alcoholic fatty liver disease (NAFLD).
NAFLD can begin in utero with longitudinal studies showing an increased risk of NAFLD in adolescents born to
obese mothers. Some features of NAFLD are similar in children and adults, yet portal fibrosis and inflammation
are more common in pediatric NASH patients than adult patients, and portends a rapid progression to end-stage
liver disease in early adulthood for reasons that remain poorly understood. Our group has spent the past decade
developing and characterizing a sophisticated nonhuman primate (NHP) model of high fat/calorically dense
maternal diet consumption that has critically important developmental and physiological similarities to humans.
Data from our well-characterized NHP model demonstrate that maternal Western-style diet (MWSD) triggers
fetal hepatic collagen deposition in the portal triad and stellate cell activation that persists in 3-year-old (3YO)
juvenile animals, despite switching to a healthy chow diet at weaning. Notably, 2 miRNAs with critical roles in
liver metabolism and inflammatory responses were significantly increased (miR-122) or decreased (miR-34a) in
fetal liver and partially normalized when obese mothers were switched to a healthy chow diet. Our results suggest
these miRNAs are diet-sensitive and candidate targets for epigenetic priming of NAFLD early in life. Our
preliminary data in 3YO NHP offspring also show that MWSD reprograms hematopoietic stem cell progenitors
(HSPC)s and bone marrow derived macrophages (BMDM) to a glycolytic phenotype and a blunted response to
IL-4, suggesting decreased anti-inflammatory capacity and impaired Mφ ability to assume a reparative
phenotype. Given the importance of M2-like Mφ for healing liver injury,our overall hypothesis is that MWSD alters
miRNAs in liver in parallel with epigenetically reprogrammed HSPC and liver Mφ before birth. This leads to
ongoing production of hyper-inflammatory Mφ and the inability to resolve liver injury across the lifespan. The
overarching goal of this proposal is to understand the mechanistic basis by which MWSD drives epigenetic
remodeling and the pathogenesis for NAFLD beginning in utero. In this revised application, our Aims are to: 1)
Test the hypothesis that MWSD alters binding of fetal miR-34a, and miR-122 to specific targets in fetal liver, and
identify macrophage sub-sets in Juvenile livers using single cell RNAseq; 2) Test the hypothesis that MWSD
drives pro-inflammatory functions in isolated fetal and 3YO HSPC and liver Mφ through distinct transcriptional
and epigenetic mechanisms. 3) Test the hypothesis that MWSD disrupts BA signaling and HNF4α in MWSD
hepatocytes and preferentially affects periportal hepatocytes in fetal and post-natal livers.Taken together, using
fetal and Juvenile NHP, which have developmental features similar to humans, we will decipher how MWSD
exposure triggers epigenetic and inflammatory modifications in HSPC and liver Mφ that drive novel pathways
underlying pediatric NAFLD.
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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JACOB E FRIEDMAN其他文献
JACOB E FRIEDMAN的其他文献
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{{ truncateString('JACOB E FRIEDMAN', 18)}}的其他基金
Center for Indigenous Resilience, Culture, and Maternal Health Equity
土著复原力、文化和孕产妇健康公平中心
- 批准号:
10748847 - 财政年份:2023
- 资助金额:
$ 60.21万 - 项目类别:
Understanding the metabolic pathology of pediatric obesity and NAFLD
了解儿童肥胖和 NAFLD 的代谢病理学
- 批准号:
10612479 - 财政年份:2022
- 资助金额:
$ 60.21万 - 项目类别:
Understanding the metabolic pathology of pediatric obesity and NAFLD
了解儿童肥胖和 NAFLD 的代谢病理学
- 批准号:
10453952 - 财政年份:2022
- 资助金额:
$ 60.21万 - 项目类别:
Maternal Obesity and Pediatric NAFLD: Fetal Origins and Long-term outcomes in Non Human Primates
母亲肥胖和儿童 NAFLD:非人类灵长类动物的胎儿起源和长期结果
- 批准号:
10646292 - 财政年份:2021
- 资助金额:
$ 60.21万 - 项目类别:
Role of the Macrophage in Developmentally Programmed NAFLD
巨噬细胞在发育程序性 NAFLD 中的作用
- 批准号:
10206128 - 财政年份:2020
- 资助金额:
$ 60.21万 - 项目类别:
Role of the Macrophage in Developmentally Programmed NAFLD
巨噬细胞在发育程序性 NAFLD 中的作用
- 批准号:
10627890 - 财政年份:2020
- 资助金额:
$ 60.21万 - 项目类别:
The Impact of Maternal Health and Diet on Development of Fetal Metabolic Systems
母亲健康和饮食对胎儿代谢系统发育的影响
- 批准号:
8703085 - 财政年份:2010
- 资助金额:
$ 60.21万 - 项目类别:
The Impact of Maternal Health and Diet on Development of Fetal Metabolic Systems
母亲健康和饮食对胎儿代谢系统发育的影响
- 批准号:
8053113 - 财政年份:2010
- 资助金额:
$ 60.21万 - 项目类别:
The Impact of Maternal Health and Diet on Development of Fetal Metabolic Systems
母亲健康和饮食对胎儿代谢系统发育的影响
- 批准号:
8147743 - 财政年份:2010
- 资助金额:
$ 60.21万 - 项目类别:
The Impact of Maternal Health and Diet on Development of Fetal Metabolic Systems
母亲健康和饮食对胎儿代谢系统发育的影响
- 批准号:
8499297 - 财政年份:2010
- 资助金额:
$ 60.21万 - 项目类别:
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