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
基本信息
- 批准号:10625938
- 负责人:
- 金额:$ 9.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AblationAddressAdultAdult ChildrenAffectAmericanAmino AcidsB-Cell DevelopmentBeta CellBindingBlood CirculationCardiovascular DiseasesCause of DeathCell physiologyChildDataDevelopmentEnvironmentEnvironmental Risk FactorFRAP1 geneFemaleFetal GrowthFetal Growth RetardationFetal LiverFetal WeightGeneticGenetic ModelsGestational AgeGestational DiabetesGlucoseGlucose IntoleranceGoalsGrantGrowthGrowth Factor ReceptorsHealthHigh Fat DietHyperinsulinismIndividualInfantInflammationInsulinInsulin ReceptorInsulin-Dependent Diabetes MellitusInsulin-Like Growth Factor ReceptorInterventionKnowledgeLeadLifeLinkLiverLongevityMalnutritionMetabolicMetabolic DiseasesMetabolic dysfunctionMetabolismModelingMolecularMultiparityNon-Insulin-Dependent Diabetes MellitusNutrientObesityOutcomePancreasPeripheralPhosphotransferasesPlacentaPre-Clinical ModelPre-EclampsiaPregnancyPregnancy ComplicationsPregnancy OutcomePublishingReproductive HealthResearchRiskRoleSignal TransductionStructure of beta Cell of isletTestingTherapeuticTimeLineTissuesUterusWomanblood glucose regulationclinical caredetection of nutrientdiet-induced obesityepidemiology studyfetalfetal programminggenetic manipulationgenetic variantglucose toleranceimprovedinsulin secretioninsulin sensitivityinsulin signalingmTOR proteinmaternal conditionmaternal obesitymouse modelobesity developmentoffspringpre-clinicalpreservationpreventresponsesuccesstrophoblast
项目摘要
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.
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Emilyn Alejandro其他文献
Emilyn Alejandro的其他文献
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{{ truncateString('Emilyn Alejandro', 18)}}的其他基金
Nutrient-sensor O-GlcNAc Transferase Regulation of Autophagy in Homeostatis of Pancreatic Beta-cell Mass and Function
营养传感器 O-GlcNAc 转移酶对胰腺 β 细胞质量和功能稳态中自噬的调节
- 批准号:
10907874 - 财政年份:2023
- 资助金额:
$ 9.3万 - 项目类别:
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:
10679756 - 财政年份:2023
- 资助金额:
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先天免疫补体系统和功能性β细胞群的发育编程
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The role of O-linked N-Acetylglucosamine Homeostasis in Pancreatic Beta-cell Development and Function
O-连接的 N-乙酰氨基葡萄糖稳态在胰腺 β 细胞发育和功能中的作用
- 批准号:
10158468 - 财政年份:2018
- 资助金额:
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The role of O-linked N-Acetylglucosamine Homeostasis in Pancreatic Beta-cell Development and Function
O-连接的 N-乙酰氨基葡萄糖稳态在胰腺 β 细胞发育和功能中的作用
- 批准号:
10406255 - 财政年份:2018
- 资助金额:
$ 9.3万 - 项目类别:
The role of O-linked N-Acetylglucosamine Homeostasis in Pancreatic Beta-cell Development and Function
O-连接的 N-乙酰氨基葡萄糖稳态在胰腺 β 细胞发育和功能中的作用
- 批准号:
9922900 - 财政年份:2018
- 资助金额:
$ 9.3万 - 项目类别:
O-linked-N-acetylglucosamine Post-translational Modification in Pancreatic Beta-cells Regulating ER Stress and Mitochondrial Function
胰腺β细胞中的O-连接-N-乙酰氨基葡萄糖翻译后修饰调节内质网应激和线粒体功能
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$ 9.3万 - 项目类别:
Mechanisms of Developmental Programing of beta-cell Susceptibility to Glucolipotoxicity
β细胞对糖脂毒性敏感性的发育规划机制
- 批准号:
9285779 - 财政年份:2014
- 资助金额:
$ 9.3万 - 项目类别:
Mechanisms of Developmental Programing of beta-cell Susceptibility to Glucolipotoxicity
β细胞对糖脂毒性敏感性的发育规划机制
- 批准号:
8804376 - 财政年份:2014
- 资助金额:
$ 9.3万 - 项目类别:
Mechanisms of Developmental Programing of beta-cell Susceptibility to Glucolipotoxicity
β细胞对糖脂毒性敏感性的发育规划机制
- 批准号:
9176214 - 财政年份:2014
- 资助金额:
$ 9.3万 - 项目类别:
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