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
• 负责人: Matthew J Dean
• 金额: $ 32.75万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725894
• 关键词: Adenylate Cyclase; Affect; Agonist; Area; Carrier Proteins; Cell Line; Cells; Circadian Rhythms; Cyclic AMP; Data; Decidua; Decidual Cell Reactions; Defect; Deposition; Diffusion; Embryo; Embryonic Development; Endometrial; Endometrial adenocarcinoma; Endometrium; Enzymes; Epithelial Cells; Epithelium; Estradiol; Fertility; Fertilization; Fibroblasts; GYS1 gene; Gene Family; Genes; Glucose; Glucose Transporter; Glycogen; Glycogen (Starch) Synthase; Glycogenesis Induction; Glycolysis; Grant; Human; IGF1 gene; Immunohistochemistry; Impairment; In Vitro; Infertility; Knock-out; Link; Litter Size; LoxP-flanked allele; Medical; Membrane; Metabolism; Mifepristone; Morula; Mus; National Institute of Child Health and Human Development; Nuclear; Nutrient; Oocytes; Ovarian; Ovarian hormone; Ovulation; Pathway interactions; Pentosephosphate Pathway; Periodic acid Schiff stain method; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Process; Production; Proestrus; Progesterone; Progesterone Receptors; Public Health; Reproduction; Research; Research Institute; Role; Sex Ratio; Signal Transduction; Site; Sodium; Source; Stains; Steroids; Testing; Time; Tissues; Uterus; Woman; blastocyst; early pregnancy; early pregnancy loss; economic cost; glucose tolerance; glucose uptake; glucose-6-phosphatase; glycogen metabolism; glycogenesis; glycogenolysis; high reward; high risk; hormone regulation; implantation; in vivo; macromolecule; mouse model; novel; nutrition; preimplantation; psychosocial; pup; reproductive; spatiotemporal; uptake

Project Summary Infertility is a significant public health problem with substantial medical, psychosocial, and economic costs. Maximal fertility in women is 30% per cycle. In most cases, the oocyte is fertilized, but the resulting embryo dies before or during implantation. During this time, embryos depend on glucose secretions into the uterine lumen. From fertilization until the morula stage, glucose uptake is low. As embryos approach the blastocyst stage, glucose uptake increases 50-fold. Similarly, endometrial decidualization is a glucose-intense process. Inhibition of the pentose phosphate pathway impairs decidualization and reduces litter size. After decidualization, the endometrium switches to Warburg metabolism to generate ATP. Defects in glucose secretion into the lumen or uptake by the decidua are linked to pregnancy complications. How the uterus meets the changing needs of the embryos and endometrium for glucose in a spatiotemporal manner is poorly understood. Our preliminary data show that the uterine endometrium can store glucose as the macromolecule glycogen in the mouse. We show that glycogen reserves in the uterine epithelium peak at proestrus and decline during the preimplantation period. The uterine epithelium expressed glucose-6-phosphatase, which is necessary for the section of glucose released from glycogen. Conversely, the glycogen content of the stroma was low and unchanging from proestrus to day post coitum (DPC) 3.5. At DPC 5.5, the glycogen content of the stroma increased 7-fold at the implantation site but remained low at the inter-implantation site. We confirmed that the decidua stores large amounts of glycogen by inducing artificial decidualization. These data indicate that the endometrium stores two distinct pools of glycogen that may serve as essential sources of glucose during pregnancy. Therefore, Aim 1 of this project is to determine if glycogen stored in the endometrium is necessary for a successful pregnancy. Using glycogen synthase 1 (GYS1) floxed mice, we will knock out glycogen synthase in the uterus using progesterone receptor (PRCre) Cre mice. After confirming a successful knockout of GYS1 and a corresponding decrease in glycogen, we will determine if these mice have regular reproductive cycles and glucose tolerance. Next, we will evaluate their fertility and determine if the lack of uterine glycogen synthase impairs the embryo's ability to establish a successful pregnancy. The pregnancy- dependent changes in glycogen content of the uterine epithelium suggest that ovarian hormones regulate glycogen in this tissue. We have already shown that estradiol-stimulated IGF1 induces glycogenesis in the uterine epithelium in vitro. Our preliminary data indicate that progesterone directly stimulates glycogen breakdown via membrane progesterone receptors. Aim 2 will elucidate the pathway by which activation of membrane progesterone receptors leads to glycogenolysis. We will then confirm the effects of estradiol and progesterone in ovariectomized mice. In summary, this research will determine if endometrial glycogen stores are required during pregnancy and assess the hormonal regulation of glycogen in the uterine epithelium.

项目摘要 不孕症是一个重大的公共卫生问题，具有巨大的医疗，心理和经济成本。 女性的最高生育率为每个周期30%。在大多数情况下，卵母细胞是受精的，但产生的胚胎 在植入前或植入过程中死亡。在此期间，胚胎依赖于葡萄糖分泌物进入子宫 流明从受精到桑椹胚阶段，葡萄糖的摄取量很低。当胚胎接近囊胚时 阶段，葡萄糖摄取增加50倍。同样，子宫内膜蜕膜化是一个葡萄糖密集的过程。 磷酸戊糖途径的抑制损害蜕膜化，并减少产仔数。后 在蜕膜化过程中，子宫内膜转变为瓦尔堡代谢以产生ATP。葡萄糖缺陷 分泌到子宫腔或被蜕膜吸收与妊娠并发症有关。子宫是如何 以时空方式满足胚胎和子宫内膜对葡萄糖不断变化的需求是很差的 明白我们的初步数据表明，子宫内膜可以储存葡萄糖作为大分子， 小鼠体内的糖原。我们发现，子宫上皮细胞中的糖原储备在发情前期达到峰值， 在胚胎植入前阶段下降。子宫上皮表达葡萄糖-6-磷酸酶，即 从糖原中释放出葡萄糖所必需的部分。相反，基质的糖原含量 从发情前期到发情后第3.5天（DPC），低且无变化。在DPC 5.5时， 在植入部位基质增加7倍，但在植入间部位保持较低。我们证实 蜕膜通过诱导人工蜕膜化来储存大量糖原。这些数据表明 子宫内膜储存两种不同的糖原，可能是葡萄糖的重要来源 孕期因此，本项目的目的1是确定储存在子宫内膜中的糖原是否 成功怀孕的必要条件。使用糖原合成酶1（GYS 1）基因敲除小鼠，我们将敲除 使用孕酮受体（PRCre）Cre小鼠在子宫中的糖原合酶。在确认成功后， 敲除GYS 1和相应的糖原减少，我们将确定这些小鼠是否有规律的 生殖周期和葡萄糖耐量。接下来，我们将评估他们的生育能力，并确定是否缺乏 子宫糖原合酶损害胚胎成功怀孕的能力。怀孕- 子宫上皮糖原含量的依赖性变化表明，卵巢激素调节 在这个组织中的糖原。我们已经证明雌二醇刺激的IGF 1可以诱导胰岛细胞中的糖原生成。 体外子宫上皮细胞。我们的初步数据表明黄体酮直接刺激糖原 通过膜孕酮受体分解。Aim 2将阐明激活 膜孕酮受体导致糖原分解。然后我们将证实雌二醇的作用， 孕酮在卵巢切除小鼠。总之，这项研究将确定是否子宫内膜糖原储存 在怀孕期间是必需的，并评估子宫上皮糖原的激素调节。