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

胎盘胰岛素信号传导和 mTOR 营养感应编程对后代代谢健康的影响

• 批准号: 10625938
• 负责人: Emilyn Alejandro
• 金额: $ 9.3万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625938
• 关键词: Ablation; Address; Adult; Adult Children; Affect; American; Amino Acids; B-Cell Development; Beta Cell; Binding; Blood Circulation; Cardiovascular Diseases; Cause of Death; Cell physiology; Child; Data; Development; Environment; Environmental Risk Factor; FRAP1 gene; Female; Fetal Growth; Fetal Growth Retardation; Fetal Liver; Fetal Weight; Genetic; Genetic Models; Gestational Age; Gestational Diabetes; Glucose; Glucose Intolerance; Goals; Grant; Growth; Growth Factor Receptors; Health; High Fat Diet; Hyperinsulinism; Individual; Infant; Inflammation; Insulin; Insulin Receptor; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor Receptor; Intervention; Knowledge; Lead; Life; Link; Liver; Longevity; Malnutrition; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Modeling; Molecular; Multiparity; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Outcome; Pancreas; Peripheral; Phosphotransferases; Placenta; Pre-Clinical Model; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Publishing; Reproductive Health; Research; Risk; Role; Signal Transduction; Structure of beta Cell of islet; Testing; Therapeutic; TimeLine; Tissues; Uterus; Woman; blood glucose regulation; clinical care; detection of nutrient; diet-induced obesity; epidemiology study; fetal; fetal programming; genetic manipulation; genetic variant; glucose tolerance; improved; insulin secretion; insulin sensitivity; insulin signaling; mTOR protein; maternal condition; maternal obesity; mouse model; obesity development; offspring; pre-clinical; preservation; prevent; response; success; trophoblast

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.

抽象的 2型糖尿病（T2D）影响十分之一的美国人，是第七大死亡原因。显然，两者都 遗传和环境因素有助于T2D。流行病学研究表明 胎儿环境和婴儿的生长不良（例如胎儿生长限制或过度生长），最终 肥胖，T2D和心血管疾病的发展后来。出生体重之间的牢固联系 T2D的风险是U形的风险，因此，两个孩子出生的孩子都面临胎龄，而胎龄则有危险。 我们建议MTORC1的母体胰岛素和胎盘营养素感应是关键的调节剂 后代的代谢健康计划。胎盘响应孕产妇的变化 环境并将母体信号整合到胎盘功能，部分由生长因子受体（例如 胰岛素受体和营养感应蛋白MTOR激酶。尽管进行了多年的研究，但孕产妇的角色 后代代谢健康中的胰岛素和胎盘mTOR未经测试，我们有模型 和专业知识以解决知识的差距。这笔赠款的第一个目标是在 母体胰岛素和后代的代谢健康。在AIM 1中，我们将确定胎盘的作用 在后代使用功能研究的代谢健康轨迹编程中的胰岛素信号传导 临床前妊娠并发症的临床前遗传模型（妊娠期母体高胰岛素血症的增加 或胰岛素受体的胎盘特异性丧失）。其次，该建议旨在确定基本机制 通过胎盘营养感应MTOR对周围胰岛素敏感性的发展编程。在AIM 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 使用鼠模型损失或胎盘中MTOR信号的增益的后代。因此，我们的研究 将确定孕产妇高胰岛素血症是否足以推动代谢健康的MAL编程 多个女性的后代。其次，我们将确定增强胎盘MTORC1是否是可行的 在成人后代保留胰岛素敏感性的治疗策略并预防长期代谢 功能障碍。了解母体胰岛素对后代代谢健康的编程影响 在阐明胰岛素治疗对妊娠糖尿病妇女的儿童的影响方面将是重要的， T1D和T2D在怀孕期间，从而提高了临床护理。该项目的预期成功将 在改善妇女的生殖健康和妊娠结局方面具有重要意义。