Gene-environment interaction in islet serotonin metabolism and impacts on maternal glucose homeostasis
胰岛血清素代谢中的基因-环境相互作用及其对母体葡萄糖稳态的影响
基本信息
- 批准号:10634224
- 负责人:
- 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
- 起止时间:2023-07-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 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
项目摘要
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.
摘要
妊娠期糖尿病的特征是在妊娠期间慢性母体高血糖,
糖尿病的诊断它是一种非常常见的产科并发症,影响全球约10-25%的孕妇。
因为患有妊娠糖尿病的女性更容易出现其他妊娠并发症,
对于妊娠期或早产儿,并发展为II型糖尿病,妊娠期糖尿病构成严重威胁
为了母亲和婴儿的健康。虽然已经确定了一些风险因素,但潜在的机制
是复杂的,确切的病因知之甚少。最近的研究表明胰腺血清素
信号传导在母体葡萄糖稳态中起关键作用。胰腺中血清素合成增加
胰岛是促进β细胞增殖和增加胰岛素分泌的关键事件,
预防孕妇孕期高血糖。降低胰岛血清素的饮食和遗传因素
合成与小鼠妊娠期糖尿病有因果关系。我们的初步研究表明,低剂量
暴露于全氟辛酸(PFOA)与血清素丰度降低有关,
妊娠C57 BL/6小鼠胰腺中的辅因子维生素B6。这些结果是一致
流行病学调查结果表明,孕妇接触PFOA与母体高血糖、胰岛素
抵抗和葡萄糖耐受不良。有趣的是,暴露于PFOA的DBA/2 J小鼠不会发生妊娠,
糖尿病C57 BL/6和DBA/2 J小鼠代谢维生素B6的能力不同,这是由于以下因素的差异:
碱性磷酸酶(ALP)活性。这些结果表明,环境胁迫诱导的
妊娠期糖尿病受遗传背景调节,较高的内源性维生素B6水平赋予妊娠期糖尿病患者
保护总的假设是,怀孕小鼠接触PFOA与妊娠相关。
通过干扰母体胰岛中5-羟色胺代谢的机制和影响
受维生素B6生物利用度的遗传差异调节。我们建议研究β细胞
在对照组和暴露于PFOA的妊娠C57 BL/6小鼠中,
妊娠期糖尿病是否与β细胞扩增减少和胰岛素减少有因果关系,
分泌物我们还希望研究在DBA/2 J妊娠小鼠中用ALP抑制剂治疗是否
减少胰岛中的维生素B6,导致对妊娠糖尿病的保护作用丧失。最后为
确定妊娠和妊娠期糖尿病如何影响胰岛编程,我们将进行RNA
测序和靶下切割和标签化,然后测序,以研究
转录组和表观基因组响应生理变化和疾病。拟议的研究将
提供关于妊娠糖尿病潜在机制的知识,以利于公众健康。
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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Martha Susiarjo其他文献
Martha Susiarjo的其他文献
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{{ item.author }}
{{ truncateString('Martha Susiarjo', 18)}}的其他基金
Tetrabromobisphenol A (TBBPA) as a modulator of tryptophan catabolism and maternal-fetal health
四溴双酚 A (TBBPA) 作为色氨酸分解代谢和母婴健康的调节剂
- 批准号:
10543084 - 财政年份:2019
- 资助金额:
$ 52.16万 - 项目类别:
Tetrabromobisphenol A (TBBPA) as a modulator of tryptophan catabolism and maternal-fetal health
四溴双酚 A (TBBPA) 作为色氨酸分解代谢和母婴健康的调节剂
- 批准号:
10321264 - 财政年份:2019
- 资助金额:
$ 52.16万 - 项目类别:
Tetrabromobisphenol A (TBBPA) as a modulator of tryptophan catabolism and maternal-fetal health
四溴双酚 A (TBBPA) 作为色氨酸分解代谢和母婴健康的调节剂
- 批准号:
9904631 - 财政年份:2019
- 资助金额:
$ 52.16万 - 项目类别:
Effects of Fetal Bisphenol A Exposure on Mouse Epigenome
胎儿双酚 A 暴露对小鼠表观基因组的影响
- 批准号:
9188560 - 财政年份:2015
- 资助金额:
$ 52.16万 - 项目类别:
Effects of fetal bisphenol A exposure on mouse epigenome
胎儿双酚 A 暴露对小鼠表观基因组的影响
- 批准号:
8599457 - 财政年份:2012
- 资助金额:
$ 52.16万 - 项目类别:
Effects of fetal bisphenol A exposure on mouse epigenome
胎儿双酚 A 暴露对小鼠表观基因组的影响
- 批准号:
8424594 - 财政年份:2012
- 资助金额:
$ 52.16万 - 项目类别:
Effects of Bisphenol A Exposure on Genomic Imprinting in the Mouse
双酚 A 暴露对小鼠基因组印记的影响
- 批准号:
8113986 - 财政年份:2010
- 资助金额:
$ 52.16万 - 项目类别:
Effects of Bisphenol A Exposure on Genomic Imprinting in the Mouse
双酚 A 暴露对小鼠基因组印记的影响
- 批准号:
8299183 - 财政年份:2010
- 资助金额:
$ 52.16万 - 项目类别:
Effects of Bisphenol A Exposure on Genomic Imprinting in the Mouse
双酚 A 暴露对小鼠基因组印记的影响
- 批准号:
7998628 - 财政年份:2010
- 资助金额:
$ 52.16万 - 项目类别:
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