CATECHOLESTROGENS AND PROLACTIN IN REGULATING UTERINE GLYCOGEN METABOLISM, MINK

儿茶酚雌激素和催乳素调节子宫糖原代谢，水貂

• 批准号: 8359685
• 负责人: JACK C ROSE
• 金额: $ 4.32万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359685
• 关键词: 2-hydroxyestradiol; 4-OH-E(2); Blood; Blood Circulation; Breeding; Catabolism; Catechol Estrogens; Data; Development; Diapause; Embryo; Energy-Generating Resources; Enzymes; Estradiol; Estrogen Receptors; Estrus; Exhibits; Funding; Glucose; Glycogen; Glycogen (Starch) Synthase; Glycogen Phosphorylase; Glycogen Synthase Kinases; Grant; Half-Life; Hormones; Human; Idaho; Immunoblotting; Litter Size; Measures; Mink; Muscle Form Glycogen Phosphorylase; National Center for Research Resources; Ovulation; Partner in relationship; Pathway interactions; Pattern; Phase; Phosphorylases; Phosphorylation; Plasma; Principal Investigator; Production; Progesterone; Prolactin; Prolactin Receptor; Reproduction; Research; Research Infrastructure; Resources; Rodent; Source; Testing; Time; United States National Institutes of Health; Uterus; blastocyst; cost; design; glycogen metabolism; implantation; natural Blastocyst Implantation; programs; reproductive

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Uterine glycogen (GLY) reserves are a potential source of energy for embryo survival, development, and implantation. Synthesis of GLY is stimulated by estradiol-17¿ (E2) in a reproductive cycle-dependent pattern, being highest during the uterine secretory phase in human's and between proestrous and estrous in rodents. Mink, are seasonal breeder's, that exhibit obligate embryonic diapause resulting in delayed implantation where, depending on the date of breeding, blastocysts may be 60 days old at implantation. Uterine GLY accumulation and mobilization to glucose may be requisite to blastocyst survival, activation (ie: termination of diapause), and implantation in this species. Plasma E2 levels in mink peak on the day of mating-induced ovulation, and again near the time of implantation. In addition, the uterus metabolizes E2 to catecholestrogens (CE) such as 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2). Previously, we have shown that E2 and CEs increase uterine GLY concentrations 6-fold in ovariectomized (OVX) mink. These hormones simultaneously reduced the expression of uterine Glycogen Synthase Kinase-3¿ (GSK-3¿), an enzyme that phosphorylates and inactivates Glycogen Synthase (GS). Because GS is rate limiting in GLY synthesis, the reduction in GSK-3¿ expression, should remove inhibition on GS resulting in increased GLY production. Both E2 and 4-OHE2 promote the phosphorylation and inactivation of GSK-3¿, further enhancing GLY synthesis. Also, 4-OHE2 and 2-OHE2 increased uterine GS expression while reducing expression of the GLY catabolizing enzyme GLY-Phosphorylase (GP), which also increases uterine GLY accumulation. Because of their very short half-live's, the effects of CE's are localized and not detectable in the blood. In addition to E2, prolactin (PRL) is essential to implantation in mink through its luteotropic actions increasing progesterone (P4) levels in the circulation. Moreover, PRL receptors have been identified in the mink uterus, suggesting that direct uterotropic actions by the hormone may also promote blastocyst implantation. We hypothesize that PRL increases GLY catabolism, providing glucose for blastocyst activation, implantation, and contribute to increased litter sizes. We will test this hypothesis in three specific aims designed to determine (1) the effects of E2, 4-OHE2, and 2-OHE2 on the phosphorylation of GS and GP; (2) if 4-OHE2 & 2-OHE2 act on the uterus through pathways independent from E2; and (3) if PRL has glycogenolytic actions in the mink uterus. Immunoblots will be used in specific aim 1. For Aim 2, mink will be treated with the estrogen receptor antagonist ICN -182,780, alone and in combination with E2, 4-OHE2, or 2-OHE2 and uterine GLY levels will be measured. For Aim 3, mink will be made hyperprolactinemic using the dopaminergic antagonisthaloperidol (HAL) and uterine GLY concentrations measured. Data from these studies will contribute to our understanding of efficient reproduction in mink.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供 该子项目的主要支持。 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源的子项目可能列出的总成本。 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 子宫糖原 (GLY) 储备是胚胎存活、发育和植入的潜在能量来源，GLY 的合成受 estradiol-17 刺激。 (E2) 依赖于生殖周期的模式，在人类的子宫分泌期以及啮齿动物的发情前期和发情期之间最高，是季节性繁殖者的，表现出专性胚胎滞育，导致植入延迟，具体取决于植入的日期。繁殖时，囊胚在植入时可能已经有 60 天了。子宫 GLY 的积累和葡萄糖的动员可能是囊胚存活和激活所必需的。 （即：滞育终止），并且在该物种中，血浆 E2 水平在交配诱导排卵当天达到峰值，并在接近着床时再次达到峰值。此外，子宫将 E2 代谢为儿茶酚雌激素 (CE)。作为 2-羟基雌二醇 (2-OHE2) 和 4-羟基雌二醇 (4-OHE2) 之前，我们已经证明 E2 和 CE 会增加。去势 (OVX) 水貂的子宫 GLY 浓度增加了 6 倍，这些激素同时降低了子宫糖原合成酶激酶 - 3 的表达。 (GSK-3¿)，一种磷酸化糖原合成酶 (GS) 并使其失活的酶，因为 GS 限制 GLY 合成，因此 GSK-3¿ 的减少。表达，应消除对 GS 的抑制，导致 GLY 产量增加，E2 和 4-OHE2 均促进 GSK-3 的磷酸化和失活。 ，进一步增强 GLY 合成，此外，4-OHE2 和 2-OHE2 增加子宫 GS 表达，同时减少 GLY 分解代谢酶 GLY 磷酸化酶 (GP) 的表达，这也增加子宫 GLY 积累，因为它们的半衰期很短。 CE 的作用是局部的，在血液中无法检测到 除了 E2 之外，催乳素 (PRL) 对于通过其在水貂体内的植入也至关重要。此外，在水貂子宫中发现了 PRL 受体，这表明该激素的直接促子宫作用也可能促进囊胚着床，我们发现 PRL 会增加 GLY 分解代谢，为囊胚提供葡萄糖。我们将在三个具体目标中测试这一假设，以确定 (1) E2、4-OHE2 和的影响。 2-OHE2 对 GS 和 GP 磷酸化的影响；(2) 4-OHE2 和 2-OHE2 是否通过独立于 E2 的途径作用于子宫；以及 (3) PRL 是否在水貂子宫中具有糖原分解作用。具体目标 1. 对于目标 2，将用雌激素受体拮抗剂 ICN -182,780 单独或与雌​​激素受体拮抗剂联合治疗水貂。对于目标 3，将测量 E2、4-OHE2 或 2-OHE2 和子宫 GLY 水平，使用多巴胺能拮抗剂哌啶醇 (HAL) 使水貂产生高催乳素血症，这些研究的数据将有助于我们了解子宫 GLY 浓度。水貂的高效繁殖。