Deciphering the Roles of Endometrial Glycogen Reserves and the Impact of Obesity on Fertility
解读子宫内膜糖原储备的作用以及肥胖对生育力的影响
基本信息
- 批准号:10638028
- 负责人:
- 金额:$ 37.29万
- 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:2023-05-08 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:AMHR2 geneAddressAffectAreaC-PeptideC57BL/6 MouseCircadian RhythmsDataDeciduaDecidual Cell ReactionsDefectDiestrusDietEmbryoEmbryonic DevelopmentEndometrialEndometrial Stromal CellEndometriumEnsureEnzymesEpitheliumEstradiolFat-Restricted DietFatty acid glycerol estersFertilityFertilizationGYS1 geneGlobal ChangeGlucoseGlucose TransporterGlycogenGlycogen PhosphorylaseGlycolysisGrowth FactorHigh Fat DietHormonalHumanHyperglycemiaHyperinsulinismHypoxiaImmunohistochemistryImpairmentIn VitroInfertilityInsulinInvadedKnock-outLactoferrinLengthLinkLitter SizeLoxP-flanked alleleMetabolismModelingMorulaMusNational Institute of Child Health and Human DevelopmentNutrientObesityPathogenesisPlacentationPre-implantation Embryo DevelopmentPregnancyPregnancy OutcomePregnancy lossProcessProestrusProgesteroneRegulationReproductionResearchRoleSerumSiteSpainTimeTissuesUterusWomanblastocystdiet-induced obesityearly pregnancyearly pregnancy lossendometrial stromafasting glucoseglucose metabolismglucose uptakeglucose-6-phosphataseglycogen metabolismhuman dataimplantationmacromoleculematernal obesitymetabolomicsmouse modelnatural Blastocyst Implantationnovelnutritionpregnancy failurepreimplantationreproductiveresponsespatiotemporaltreatment group
项目摘要
Project Summary
Over 40% of pregnancies fail in women, most before or during embryo implantation. During this time, embryos
are dependent on secretions into the uterine lumen that contains all of the growth factors and nutrients
necessary for embryo development. In particular, embryos need glucose. From fertilization until the morula
stage, glucose uptake is low, but without glucose, the embryo degenerates. As embryos approach the
blastocyst stage, glucose uptake increases dramatically, providing ATP to the embryo within the hypoxic
uterine lumen. The endometrial stroma also uses a large amount of glucose to decidualize. After
decidualization, the stroma relies on Warburg metabolism to produce ATP and supplies glucose to the invading
embryo. Thus, it is clear that glucose availability must be regulated in a spatiotemporal manner to ensure a
successful pregnancy. Finally, obesity leads to reduced fertility in women through, in part, effects on the uterus
and its ability to support pregnancy. Most research on endometrial glucose has focused on the role of glucose
transporters. However, the endometrium can also transiently store glucose as the macromolecule glycogen. In
women, endometrial glycogen concentrations are correlated with fertility, but a direct link between uterine
glycogen and fertility has never been established. To investigate this in mice, we collected uteri on proestrus
and days post coitum (DPC) 1.5, 3.5, and 5.5. Our preliminary data show that the mouse endometrium stores
two distinct glycogen pools: in the uterine epithelium and the uterine decidua. Epithelial glycogen peaked at
proestrus and significantly reduced during the preimplantation period. The epithelial expressed glycogen
phosphorylase and glucose-6-phosphatase, suggesting the epithelium can catabolize glycogen and secrete
the resulting glucose. In contrast, the endometrial stroma stored little glycogen until decidualization, when
glycogen content increased 7-fold. Similarly, artificially induced decidualization in hormonally primed mice
resulted in a 5-fold increase in glycogen levels. In order to establish a definitive relationship between these
distinct pools of glycogen and fertility, we obtained glycogen synthase 1 (GYS1) floxed mice so that we can
knockout GYS1 in a tissue-specific manner. Aim 1 will generate an LTFiCre/+ GYS1flox/flox mouse to study the role
of epithelial glycogen in glucose secretion and preimplantation embryo survival. Aim 2 will use AMHR2Cre/+
GYS1flox/flox mice to study the role of glycogen in the decidua. Collectively these aims will establish a causative
link between the ability of the uterus to store glycogen in the epithelium and decidua and fertility. Aim 3 will use
a diet-induced obesity model to study how maternal obesity affects glycogen metabolism in the mouse uterus.
We will determine how a 45% and 60% fat diet affects uterine metabolism and fertility in a C57BL/6 mouse
model. In vitro, we will determine the effects of hyperglycemia and hyperinsulinemia on decidual glycogen. In
summary, this research will evaluate the role of endometrial glycogen stores in support of early pregnancy and
assess the potential for maternal obesity to result in dysfunctional endometrial glycogen metabolism.
项目总结
项目成果
期刊论文数量(0)
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Matthew J Dean其他文献
Matthew J Dean的其他文献
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{{ truncateString('Matthew J Dean', 18)}}的其他基金
The Role of Uterine Glycogen in Establishing a Successful Pregnancy
子宫糖原在成功怀孕中的作用
- 批准号:
10725894 - 财政年份:2023
- 资助金额:
$ 37.29万 - 项目类别:
Propylparaben effects on reproductive health of the aging female
对羟基苯甲酸丙酯对老年女性生殖健康的影响
- 批准号:
10373441 - 财政年份:2021
- 资助金额:
$ 37.29万 - 项目类别:
Propylparaben effects on reproductive health of the aging female
对羟基苯甲酸丙酯对老年女性生殖健康的影响
- 批准号:
10526421 - 财政年份:2021
- 资助金额:
$ 37.29万 - 项目类别:
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