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 不孕症是大量医疗，社会心理和经济成本的重大公共卫生问题。 女性最大生育能力为每个周期30％。在大多数情况下，卵母细胞受精，但产生的胚胎 植入之前或期间死亡。在此期间，胚胎依赖于子宫的葡萄糖分泌物 流明。从受精到莫拉拉阶段，葡萄糖吸收率低。当胚胎接近胚泡 阶段，葡萄糖摄取增加了50倍。同样，子宫内膜deDIADAILIAD是一个葡萄糖强度过程。 抑制戊糖磷酸盐途径会损害脱骨化并减少垃圾大小。后 固定化，子宫内膜转向Warburg代谢产生ATP。葡萄糖缺陷 Decidua向管腔的分泌或吸收与妊娠并发症有关。子宫如何 满足胚胎和子宫内膜对葡萄糖的需求不断变化的时空方式很差 理解。我们的初步数据表明，子宫内膜可以将葡萄糖储存为大分子 小鼠中的糖原。我们表明，糖原储备在促E的子宫上皮峰和 在植入前时期下降。子宫上皮表达的葡萄糖-6-磷酸酶，这是 对于从糖原释放的葡萄糖部分所必需的。相反，基质的糖原含量 从前弹力到日间涂层（DPC）3.5较低且不变。在DPC 5.5时，糖原含量 基质在植入部位增加了7倍，但在植入部位保持较低。我们确认 Decidua通过诱导人造deDIDAUTIATION来存储大量糖原。这些数据表明 子宫内膜存储两个不同的糖原池，这些糖原可能是葡萄糖的重要来源 怀孕期间。因此，该项目的目标1是确定子宫内膜中存储的糖原是否是 成功怀孕所必需的。使用糖原合酶1（Gys1）floxed小鼠，我们将淘汰 使用孕酮受体（PRCRE）CRE小鼠在子宫中的糖原合酶。确认成功之后 Gys1的敲除和糖原的相应降低，我们将确定这些小鼠是否有规则 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 子宫糖原合酶会损害胚胎成功妊娠的能力。怀孕 - 子宫上皮糖原含量的依赖性变化表明卵巢激素调节 该组织中的糖原。我们已经表明，雌二醇刺激的IGF1在 子宫上皮在体外。我们的初步数据表明孕酮直接刺激糖原 通过膜孕酮受体分解。 AIM 2将阐明激活的途径 膜孕酮受体导致糖原分解。然后，我们将确认雌二醇和 卵巢切除小鼠的孕酮。总而言之，这项研究将确定子宫内膜糖原是否储存 在怀孕期间需要并评估子宫上皮糖原的激素调节。