Fetal glucagon links fetal metabolism with uterine blood flow and placental nutrient transfer by inhibiting placental lactogen secretion

胎儿胰高血糖素通过抑制胎盘泌乳素分泌，将胎儿代谢与子宫血流和胎盘营养物质转移联系起来

• 批准号: 10636131
• 负责人: Paul Joseph Rozance
• 金额: $ 66.12万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-13 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636131
• 关键词: Acidosis; Amino Acids; Arteries; Blood; Blood flow; Cells; Circulation; Data; Diabetes Mellitus; Disease Management; Endothelium; Ensure; Event; Fetal Diseases; Fetal Growth; Fetal Proteins; Fetal Sheep; Fetal Weight; Fetus; Glucagon; Glucose; Goals; Growth; Growth Factor; Histologic; Hormonal; Hormones; Human; Hypoxia; In Situ; In Vitro; Infusion procedures; Insulin; Insulin-Like Growth Factor I; Investigation; Knowledge; Link; Mediating; Metabolic; Metabolism; Mothers; Myometrial; Nutrient; Nutritional; Oxygen; Physiological; Placenta; Placental Insufficiency; Placental Lactogen; Placentation; Plasma; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnant sheep; Production; Publications; RNA Interference; Regulation; Role; Sheep; Signal Transduction; Techniques; Testing; Uterus; Vasodilator Agents; effective therapy; experimental study; falls; fetal; fetus hypoxia; in utero; inhibitor; lentiviral-mediated; maternal obesity; novel; nutrient metabolism; preservation; prevent; restoration; trophoblast; uptake

PROJECT ABSTRACT Our goal is to establish a new framework for understanding the regulation of fetal growth. To do so, we will demonstrate novel roles for fetal glucagon and maternal placental lactogen. Current dogma holds that the mother's nutritional and hormonal status, uterine blood flow, and early events in placental development regulate placental nutrient delivery and fetal growth. However, knowledge gaps in this understanding have prevented progress towards successful treatment of disordered fetal growth during complications of pregnancy. This proposal will show how fetal glucagon inhibits uterine blood flow and placental nutrient delivery by inhibiting secretion of placental lactogen into the maternal circulation. We have recently demonstrated that experimentally increasing fetal glucagon concentrations with direct fetal glucagon infusions into late gestation fetal sheep lowers uterine blood, placental uptake of nutrients and oxygen from the maternal circulation, placental delivery of amino acids to the fetus, fetal plasma concentrations of amino acids, fetal plasma concentrations of the anabolic growth factors insulin and IGF-1, and fetal protein accretion. These were associated with a 13% reduction in fetal weight after just a nine-day infusion. Additionally, we have demonstrated that experimentally lowering placental lactogen in pregnant sheep results in lower uterine blood flow and placental nutrient delivery independent of its classically described role in regulating maternal nutrient metabolism. We have repeatedly shown that increasing fetal amino acids raises fetal glucagon concentrations. Taken together, these data support our overarching hypothesis: fetal glucagon matches placental nutrient delivery to fetal metabolic demand by inhibiting PL secretion. This hypothesis will be tested in pregnant sheep, isolated human primary trophoblasts, and uterine and myometrial arteries isolated from pregnant sheep and humans, respectively. In Aim #1 we will show that the mechanism by which fetal glucagon inhibits fetal growth is by lowering placental amino acid delivery and fetal amino acid concentrations. In Aim #2 we will demonstrate that the mechanism by which fetal glucagon inhibits uterine blood flow and placental nutrient delivery is by lowering placental lactogen secretion. In Aim #3 we will establish the mechanism by which glucagon inhibits placental lactogen secretion. This proposal will be the first mechanistic physiological investigation into fetal glucagon as an inhibitor of uterine blood flow, placental nutrient delivery, and fetal growth and placental lactogen as a vasodilator in the uterine circulation. The impact will be to shift the paradigm for our understanding of the regulation of fetal growth. This is required if we are to make new advances into the management of disordered fetal growth in pregnancies complicated by placental insufficiency, preeclampsia, diabetes, maternal obesity and other conditions.

项目摘要 我们的目标是建立一个新的框架，以了解调节胎儿生长的调节。为此， 我们将展示胎儿胰高血糖素和母体胎盘乳酸的新作用。当前的教条 认为母亲的营养和荷尔蒙状态，子宫血流以及早期事件 胎盘发育调节胎盘养分递送和胎儿生长。但是，知识 这种理解中的差距阻止了成功治疗无序胎儿的进步 怀孕并发症期间的生长。该建议将显示胎儿胰高血糖素如何抑制子宫 血流和胎盘养分递送，通过抑制胎盘泌乳的分泌 产妇循环。我们最近证明了实验增加的胎儿胰高血糖素 直接胎儿胰高血糖素输注到晚期妊娠胎儿绵羊的浓度降低子宫血液， 营养和氧气的胎盘摄取，产妇循环，氨基的胎盘递送 到胎儿的酸，氨基酸的胎儿血浆浓度，胎儿血浆浓度的浓度 合成代谢生长因子胰岛素和IGF-1以及胎儿蛋白积聚。这些与 仅9天输注后，胎儿体重减轻了13％。此外，我们已经证明了 实验降低孕妇绵羊的胎盘泌乳因导致子宫血流降低，并且 胎盘养分的递送独立于其经典描述的作用在调节孕产妇营养中的作用 代谢。我们反复表明，增加的胎儿氨基酸会增加胎儿胰高血糖素 浓度。综上所述，这些数据支持我们的总体假设：胎儿胰高血糖素 通过抑制PL分泌，将胎盘养分递送到胎儿代谢需求。这 假设将在怀孕绵羊，孤立的人类原发性滋养层和子宫和子宫和 分别从怀孕的绵羊和人类中分离出的肌层动脉。在AIM＃1中，我们将显示 胎儿胰高血糖素抑制胎儿生长的机制是通过降低胎盘氨基酸的 递送和胎儿氨基酸浓度。在AIM＃2中，我们将证明该机制 哪种胎儿胰高血糖素抑制子宫血流和胎盘养分的递送是通过降低胎盘 乳原分泌。在AIM＃3中，我们将建立胰高血糖素抑制胎盘的机制 乳原分泌。该建议将是对胎儿的首次机械生理研究 胰高血糖素是子宫血流，胎盘营养递送和胎儿生长的抑制剂 子宫循环中的胎盘乳酸作为血管扩张剂。影响是改变范式 为了理解调节胎儿生长。如果我们要新的话，这是必需的 胎盘复杂的妊娠胎儿生长的管理不断发展 功能不全，先兆子痫，糖尿病，孕产妇肥胖和其他疾病。