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来理解胎儿生长的调节。要做到这一点， 我们将展示胎儿胰升糖素和母体胎盘催乳素的新作用。当前的教条 认为母亲的营养和荷尔蒙状况、子宫血流和早期事件 胎盘发育调节胎盘营养物质的输送和胎儿的生长。然而，知识 这一认识上的差距阻碍了成功治疗胎儿疾病的进展 妊娠并发症期间的生长发育。这项提案将展示胎儿胰高血糖素如何抑制子宫 抑制胎盘催乳素分泌到胎盘的血流和胎盘营养输送 母体循环。我们最近证明，实验性地增加胎儿胰高血糖素 将胎儿胰升糖素直接注入妊娠晚期的绵羊可降低子宫血液的浓度， 胎盘从母体循环中摄取营养物质和氧气，胎盘交付氨基 酸对胎儿、胎儿血浆中氨基酸浓度、胎儿血浆中 合成生长因子胰岛素和胰岛素样生长因子-1与胎儿蛋白质增加。这些都与一个 仅用了9天的输液，胎儿体重就减轻了13%。此外，我们已经证明了 实验性降低妊娠绵羊胎盘催乳素导致子宫血流量降低和 胎盘营养递送独立于其经典描述的调节母体营养的作用 新陈代谢。我们一再表明，增加胎儿氨基酸会提高胎儿胰高血糖素 浓度。综上所述，这些数据支持我们的首要假设：胎儿胰高血糖素 通过抑制磷脂酶的分泌，使胎盘营养物质的输送与胎儿的代谢需求相匹配。这 假说将在怀孕的绵羊、分离的人类初级滋养层细胞和子宫和 分别从怀孕的绵羊和人分离出肌层动脉。在Aim#1中，我们将展示 胎儿胰升糖素抑制胎儿生长的机制是通过降低胎盘氨基酸 分娩和胎儿氨基酸浓度。在目标2中，我们将通过以下方式证明该机制 胎儿胰高血糖素抑制子宫血流和胎盘营养输送是通过降低胎盘 催乳素分泌。在目标3中，我们将建立胰高血糖素抑制胎盘的机制 催乳素分泌。这项提议将是第一次对胎儿进行机械生理研究 作为子宫血流、胎盘营养输送和胎儿生长发育抑制物的高血糖素 胎盘催乳素在子宫循环中作为血管扩张剂。其影响将是改变范式 为我们理解胎儿生长发育的调节机制。如果我们要制作新的，这是必需的 妊娠合并胎盘的胎儿生长紊乱的治疗进展 功能不全、先兆子痫、糖尿病、母体肥胖等情况。