Placental Insulin Signaling and mTOR Nutrient-Sensing Programming of Offspring Metabolic Health

摘要 2型糖尿病（T2D）影响近十分之一的美国人，是第七大死亡原因。肯定两 遗传和环境因素导致T2D。流行病学研究表明， 不良的胎儿环境和婴儿生长（例如，胎儿生长受限或过度生长）以及最终 肥胖、T2D和心血管疾病的发展。出生体重与 T2D的风险是U形的，因此，出生时小于胎龄的儿童和出生时大于胎龄的儿童都有风险。 我们认为母体胰岛素和mTORC1的胎盘营养感应是这一过程的关键调节因子。 后代的代谢健康规划。胎盘对母体的变化有反应， 环境，并通过生长因子受体将母体信号部分整合到胎盘功能中， 胰岛素受体和营养感应蛋白mTOR激酶。尽管多年的研究，产妇的作用， 胰岛素和胎盘mTOR在后代代谢健康中的作用未经测试， 和专业知识来填补这一知识空白。这项补助金的第一个目标是建立一个因果关系， 母体胰岛素和后代的代谢健康。在目标1中，我们将确定胎盘的作用， 胰岛素信号在后代代谢健康轨迹规划中的作用 妊娠并发症的临床前遗传模型（妊娠期间母体高胰岛素血症的获得 或胰岛素受体的胎盘特异性损失）。第二，本建议旨在确定 胎盘营养感应mTOR对外周胰岛素敏感性的发育编程。在目标2中， 我们将通过胎盘mTORC1营养感应来确定胰岛素敏感性的机制， 使用胎盘中mTOR信号传导丢失或获得的鼠模型的后代。因此，我们的研究 将确定母体高胰岛素血症是否足以驱动代谢健康的不良编程， 多产雌性的后代。其次，我们将确定增强胎盘mTORC1是否是一种可行的方法。 在成年后代中保持胰岛素敏感性和防止长期代谢的治疗策略 功能障碍了解母体胰岛素对后代代谢健康的影响 将对阐明胰岛素治疗对妊娠期糖尿病妇女的子女的影响具有重要意义， 妊娠期T1D和T2D，从而促进临床护理。该项目的预期成功将 对改善妇女的生殖健康和怀孕结果具有重大意义。

Abstract Type 2 diabetes (T2D) affects nearly 1 in 10 Americans and is the 7th leading cause of death. It is clear that both genetic and environmental factors contribute to T2D. Epidemiological studies show robust associations between poor fetal environment and infant growth (e.g. fetal growth-restriction or over-growth) and the eventual development of obesity, T2D, and cardiovascular disease later in life. The strong association between birthweight and risk of T2D is U-shaped, thus, both children born small and those born large for gestational age are at risk. We propose that maternal insulin and placental nutrient-sensing by mTORC1 are critical regulators of the metabolic health programming of the offspring. The placenta responds to changes in the maternal environment and integrates maternal signals to placental function in part by growth factor receptors such as the insulin receptor, and the nutrient-sensing protein mTOR kinase. Despite years of research, the roles for maternal insulin and placental mTOR in the metabolic health of the offspring are untested, and we have the model and expertise to address this gap in knowledge. The first goal of this grant is to establish a causal link between maternal insulin and the metabolic health of the offspring. In Aim 1, we will determine the roles of placental insulin signaling in the programming of metabolic health trajectory in the offspring using functional studies with preclinical genetic models of pregnancy complications (gain of maternal hyperinsulinemia during pregnancy or placenta-specific loss of insulin receptor). Second, this proposal aims to identify the mechanisms underlying the developmental programming of peripheral insulin sensitivity by placental nutrient-sensing mTOR. In Aim 2, we will determine mechanisms of insulin sensitivity by placental mTORC1 nutrient-sensing in the offspring using murine models with loss or gain of mTOR signaling in the placenta. Therefore, our studies will determine if maternal hyperinsulinemia is sufficient to drive mal programming of metabolic health in the offspring in multiparous females. Second, we will determine if enhancing placental mTORC1 is a feasible therapeutic strategy for preserving insulin sensitivity in the adult offspring and preventing long-term metabolic dysfunction. Understanding the programming impact of maternal insulin on the metabolic health of the offspring will be significant in illuminating the effects of insulin therapy on the children of women with gestational diabetes, T1D, and T2D during pregnancy, thereby advancing clinical care. The anticipated success of this project will have significant implications in improving women's reproductive health and pregnancy outcomes.