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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 子宫糖原（GLY）储量是胚胎生存，发育和植入的潜在能源。雌二醇-17（E2）以复制循环依赖性模式刺激了Gly的合成，在人类的子宫秘密阶段以及啮齿动物中的雌性和发情之间高度高。 Mink是季节性繁殖者，表现出强大的胚胎性滞育，导致植入延迟，根据繁殖日期，胚泡时可能会在植入时60天。子宫糖的积累和葡萄糖的动员可能是胚泡生存，激活（即：抑制的终止）和该物种中的植入所必需的。在交配诱导的排卵当天，在植入时，血浆E2水平的水平。此外，子宫将E2代谢为Catecholestrogen（CE），例如2-羟基雌二醇（2-OHE2）和4-羟基雌二醇（4-OHE2）。以前，我们已经表明E2和CES在卵巢切除（OVX）貂皮中增加了子宫糖浓度6倍。这些恐怖只是降低了子宫糖原合酶-3（GSK-3¿）的表达，这是一种磷酸化并使糖原合酶（GS）失活的酶。由于GS是GLY合成的速率限制，因此GSK-3表达的降低应消除对GS的抑制，从而导致Gly产生增加。 E2和4-OHE2都促进了GSK-3¿的磷酸化和灭活，从而进一步增强了Gly合成。同样，4-OHE2和2-OHE2增加了子宫GS的表达，同时还原了Gly分解代谢酶的糖 - 磷酸酶（GP）的表达，这也增加了子宫GLY的积累。由于它们的半寿命很短，因此CE的作用是局部的，无法在血液中检测到。除E2外，催乳激素（PRL）对于在循环中提高孕酮（P4）水平的黄褐色作用而对貂的植入至关重要。此外，已经在貂子宫中鉴定出PRL受体，这表明马酮的直接子宫骨动作也可能促进胚泡植入。我们将在三个特定目的中检验该假设，旨在确定（1）E2，4-OHE2和2-OHE2对GS和GP磷酸化的影响； （2）如果4-OHE2和2-OHE2通过独立于E2的途径在子宫上作用； （3）如果PRL在貂子宫中具有糖原溶解作用。免疫印迹将用于特定的目标1。对于AIM 2，单独使用雌激素受体拮抗剂ICN -182,780，并与E2、4-OHE2或2-OHE2和子宫GLY水平进行治疗。对于AIM 3，将使用多巴胺能拮抗剂（HAL）和子宫糖浓度进行貂皮过甲乳酚。这些研究的数据将有助于我们理解貂皮中有效繁殖。