Fetal Brain-Placental Immune Activation in Maternal Obesity
母亲肥胖中胎儿脑胎盘免疫激活
基本信息
- 批准号:10229462
- 负责人:
- 金额:$ 39.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAdaptor Signaling ProteinAdolescentAdult ChildrenAffectAgeAnti-Inflammatory AgentsAntigensAnxietyAttention deficit hyperactivity disorderBehaviorBiologicalBody mass indexBrainCellsChildChronicCognitive deficitsDataDevelopmentEmbryoEncephalitisEnzyme-Linked Immunosorbent AssayEvaluationFemaleFetusFlow CytometryFrequenciesHippocampus (Brain)HumanImmuneImmune signalingIndividualInflammationInflammatoryInterventionKnowledgeLeadLearningLearning DisabilitiesLifeLinkLipopolysaccharidesLongevityMaternal ExposureMathematicsMediatingMental DepressionMicrogliaMorbidity - disease rateMusMyelogenousNeurocognitive DeficitObese MiceObesityPathogenesisPlacentaPlayPopulationPre-Clinical ModelPregnancyReadingReportingRiskRoleSalineSecondary toSentinelSex DifferencesSignal TransductionTestingTherapeuticThinnessTissuesToll-like receptorsTransgenic MiceUnited StatesWomanYolk Sacautism spectrum disorderbrain cellcell typecytokinedensitydiet-induced obesityepidemiology studyexperimental studyfetalimmune activationimmune functionimmunoreactivityin uteroinnovationmacrophagemalematernal obesitymother nutritionmouse modelneonateneurodevelopmentnovelobese mothersoffspringprogramsreproductiveresponsesexsexual dimorphismsingle-cell RNA sequencingtranscriptome
项目摘要
PROJECT SUMMARY
In the United States, one in three women of reproductive age is obese. In large epidemiologic studies, maternal
obesity is associated with cognitive deficits in children, including reduced and low IQ (<70), and lower reading
and math scores. Underlying mechanisms remain unclear. What is known is that maternal obesity is a state of
chronic low-level immune activation, and both placental and brain inflammation have been reported in fetuses
and offspring of obese women. Microglia, the resident immune cells of the brain, have been implicated in the
pathogenesis of many of the neurodevelopmental morbidities noted with increased frequency in offspring of
obese women. Despite this, there is a gap in knowledge about if/how placental inflammation affects fetal brain
development in the setting of maternal obesity. We have demonstrated sex-specific fetal brain transcriptomes in
the setting of maternal obesity, with dysregulated immune and inflammatory signaling highlighted as key effects
of maternal obesity on both the male and female embryonic brain. We subsequently demonstrated a significant
and sexually dimorphic effect of maternal obesity on microglial antigen (Iba-1) density in the embryonic
hippocampus, and hippocampal learning deficits in obesity-exposed offspring, with male offspring more
significantly affected. These data support the hypothesis that aberrant brain immune activation in embryonic life
is one mechanism underlying enduring cognitive deficits.
Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct
evaluation of microglial function in a living human fetus or neonate is impossible. Fortunately, placental
macrophages (Hofbauer cells) and microglia have a common origin in the fetal yolk sac. Yolk-sac-derived
macrophages comprise the permanent pool of brain microglia throughout an individual’s lifetime. Therefore,
placental Hofbauer cells represent a potentially novel biologic sentinel that may mirror microglial
immunoreactivity. Here, we seek to test the following hypotheses: (1a) maternal obesity will prime both Hofbauer
cells and fetal brain microglia to overrespond to an immune challenge (1b) Maternal obesity will induce key
alterations in the fetal microglial single cell transcriptome which will be recapitulated in the Hofbauer cell
transcriptome (2) Selective ablation of pro-inflammatory macrophage signaling in the fetal brain and placenta
using an innovative transgenic mouse will rescue maternal obesity-associated hippocampal learning deficits.
The proposed experiments will fill a knowledge gap by ascertaining whether increased pro-inflammatory
macrophage signaling in the placenta and fetal brain is a mechanism underlying offspring hippocampal learning
deficits in maternal obesity. Demonstrating a causal link between fetal placental and brain macrophage-mediated
inflammation and neurodevelopmental morbidity has potential therapeutic applications. If Hofbauer cells can
serve as a more accessible cell type that provides information about the behavior of fetal brain microglia, there
may be broader implications for assessing offspring risk in the setting of maternal exposures beyond obesity.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrea Goldberg Edlow其他文献
Andrea Goldberg Edlow的其他文献
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{{ truncateString('Andrea Goldberg Edlow', 18)}}的其他基金
Research Project 1 - The pregnancy ImmunOME
研究项目 1 - 妊娠 ImmunOME
- 批准号:
10611526 - 财政年份:2022
- 资助金额:
$ 39.46万 - 项目类别:
Cellular models of fetal neurodevelopment in maternal SARS-CoV-2 infection
母体 SARS-CoV-2 感染时胎儿神经发育的细胞模型
- 批准号:
10612535 - 财政年份:2022
- 资助金额:
$ 39.46万 - 项目类别:
Research Project 1 - The pregnancy ImmunOME
研究项目 1 - 妊娠 ImmunOME
- 批准号:
10420109 - 财政年份:2022
- 资助金额:
$ 39.46万 - 项目类别:
Sex Differences in Fetal Brain-Placental Immune Programming in Maternal Obesity
母亲肥胖中胎儿脑胎盘免疫编程的性别差异
- 批准号:
10093233 - 财政年份:2019
- 资助金额:
$ 39.46万 - 项目类别:
Maternal obesity and inflammation as drivers of maternal morbidity in COVID-19
孕产妇肥胖和炎症是 COVID-19 孕产妇发病的驱动因素
- 批准号:
10200505 - 财政年份:2019
- 资助金额:
$ 39.46万 - 项目类别:
Helping Us Grow Stronger (HUGS/Abrazos): COVID-19 in pregnancy and reducing toxic stress in mother-infant dyads
帮助我们变得更强 (HUGS/Abrazos):怀孕期间的 COVID-19 和减少母婴二人的毒性压力
- 批准号:
10393329 - 财政年份:2019
- 资助金额:
$ 39.46万 - 项目类别:
Fetal Brain-Placental Immune Activation in Maternal Obesity
母亲肥胖中胎儿脑胎盘免疫激活
- 批准号:
10002284 - 财政年份:2019
- 资助金额:
$ 39.46万 - 项目类别: