Gene-environment interaction in islet serotonin metabolism and impacts on maternal glucose homeostasis
Gene-environment interaction in islet serotonin metabolism and impacts on maternal glucose homeostasis
批准号:
10634224
负责人:
Martha Susiarjo
金额:
$52.16万
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
项目状态:
未结题
起止时间:
2023-07-01 至 2028-04-30
关键词:
AffectAgonistAgreementAlkaline PhosphataseAntibodiesBeta CellBindingBiological AvailabilityBiologyC57BL/6 MouseCell ProliferationChildChronicComplexCountryDataDiabetes MellitusDiagnosisDietary FactorsDiseaseDoseEndocrine DisruptorsEnvironmental ExposureEnvironmental Risk FactorEpidemiologyEtiologyEventExposure toFailureFetal healthGene ExpressionGeneticGestational DiabetesGlucose IntoleranceGoalsHealthHumanImmunofluorescence ImmunologicImpairmentInsulinInsulin ResistanceIslets of LangerhansKnowledgeLigandsLinkLiquid ChromatographyMass Spectrum AnalysisMaternal HealthMetabolicMetabolismMethodsMothersMusNational Health and Nutrition Examination SurveyNon-Insulin-Dependent Diabetes MellitusPancreasParticipantPhenotypePhysiologicalPilot ProjectsPlayPredispositionPregnancyPregnancy ComplicationsPregnant WomenPremature BirthPremature InfantProductionProliferatingPublic HealthPublishingPyridoxal PhosphateReceptor ActivationRegulationReportingResearchResolutionRiskRisk FactorsRoleSecond Pregnancy TrimesterSerotoninSerumSignal TransductionStructure of beta Cell of isletTestingVitamin AVitamin B6Vitamin B6 Metabolism PathwayWomanWorkblood glucose regulationcofactordietaryenvironmental chemicalepidemiology studyepigenomeepigenomicsfasting glucosegene environment interactionhealth of the motherhistone modificationinsightinsulin secretionisletmaternal hyperglycemiamouse modelobstetrical complicationperfluorooctanoic acidphosphatase inhibitorpregnantpreventprogramsreceptorresponseserotonin receptortranscriptometranscriptome sequencingtranscriptomics
中文摘要
摘要
英文摘要
ABSTRACT
Gestational diabetes is characterized by chronic maternal hyperglycemia during pregnancy without a prior
diagnosis of diabetes. It is a very common obstetric complication affecting ~10-25% pregnant women globally.
Because women with gestational diabetes are more likely to have other pregnancy complications, deliver large
for gestational or premature babies, and develop type II diabetes, gestational diabetes poses a serious threat
to the health of mother and baby. Although some risk factors have been defined, the underlying mechanisms
are complex and the precise etiologies are poorly understood. Recent studies show that pancreatic serotonin
signaling plays a critical role in maternal glucose homeostasis. Increased serotonin synthesis in the pancreatic
islet is a critical event that promotes beta cell proliferation and increased insulin secretion that are needed to
prevent maternal hyperglycemia during pregnancy. Dietary and genetic factors that reduce islet serotonin
synthesis are causatively linked to gestational diabetes in mice. Our preliminary studies show that low dose
exposure to perfluorooctanoic acid (PFOA) is associated with reduced abundance of serotonin and its critical
cofactor vitamin B6 in the pancreas from pregnant C57BL/6 mouse. These results are consistent with
epidemiological findings that PFOA exposure in pregnant women is linked to maternal hyperglycemia, insulin
resistance, and glucose intolerance. Interestingly, DBA/2J mice exposed to PFOA do not develop gestational
diabetes. The C57BL/6 and DBA/2J mice differ in their abilities to metabolize vitamin B6 due to differences in
activities of alkaline phosphatase (ALP). These results suggest that environmental exposure-induced
gestational diabetes is modulated by genetic background and higher endogenous vitamin B6 level confers a
protection. The overall hypothesis is that PFOA exposure in pregnant mice is causatively linked to gestational
diabetes through mechanisms that perturb serotonin metabolism in maternal pancreatic islets and the effects
are modulated by genetic differences in vitamin B6 bioavailability. We propose to investigate beta cell
proliferation and serotonin abundance in control and PFOA-exposed pregnant C57BL/6 mice to determine
whether the gestational diabetes is causatively linked to reduced beta cell expansion and reduced insulin
secretion. We also wish to investigate whether treatment with an ALP inhibitor in the DBA/2J pregnant mice will
reduce vitamin B6 in pancreatic islets and result in loss of protection to gestational diabetes. Finally, to
determine how pregnancy and gestational diabetes influence islet programming, we will perform RNA
sequencing and Cleavage Under Targets and Tagmentation followed by sequencing to study changes in the
transcriptome and epigenome in response to physiological changes and disease. The proposed research will
provide knowledge on mechanisms underlying gestational diabetes that benefit public health.
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会议论文
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批准号:10543084
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项目类别:
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资助金额:$34.65万
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财政年份:2019
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负责人:Martha Susiarjo
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依托单位:
Tetrabromobisphenol A (TBBPA) as a modulator of tryptophan catabolism and maternal-fetal health
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批准号:10321264
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项目类别:
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资助金额:$34.65万
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财政年份:2019
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负责人:Martha Susiarjo
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依托单位:
Tetrabromobisphenol A (TBBPA) as a modulator of tryptophan catabolism and maternal-fetal health
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批准号:9904631
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项目类别:
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资助金额:$34.65万
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财政年份:2019
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负责人:Martha Susiarjo
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Effects of Fetal Bisphenol A Exposure on Mouse Epigenome
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批准号:9188560
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资助金额:$24.34万
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Effects of fetal bisphenol A exposure on mouse epigenome
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资助金额:$9.95万
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负责人:Martha Susiarjo
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依托单位:
Effects of fetal bisphenol A exposure on mouse epigenome
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批准号:8424594
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资助金额:$9.95万
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Effects of Bisphenol A Exposure on Genomic Imprinting in the Mouse
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批准号:8113986
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资助金额:$5.47万
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Effects of Bisphenol A Exposure on Genomic Imprinting in the Mouse
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批准号:8299183
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项目类别:
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资助金额:$2.66万
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财政年份:2010
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负责人:Martha Susiarjo
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依托单位:
Effects of Bisphenol A Exposure on Genomic Imprinting in the Mouse
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批准号:7998628
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项目类别:
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资助金额:$5.22万
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财政年份:2010
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负责人:Martha Susiarjo
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Pilot Project Program
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资助金额:$36.78万
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财政年份:1997
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依托单位:
国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
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批准号:32000851
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项目类别:青年科学基金项目
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资助金额:24.0万元
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批准年份:2020
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负责人:乔安娜
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依托单位: