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

基本信息

  • 批准号:
    8804376
  • 负责人:
  • 金额:
    $ 13.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-01 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a major health problem worldwide. Identifying modifiable risk factors is key in decreasing the incidence and associated economic burden of T2D. Both genetic and environmental factors contribute to the development of T2D. The fetal nutrient environment during pregnancy is as a major factor that modifies the risk for developing T2D. Studies from humans and animal models show robust associations between poor fetal growth and the development of T2D due to maternal malnutrition during pregnancy, which results from permanent changes in pancreatic β-cell function and increases susceptibility to T2D. The overall research objective of this K01 proposal is to understand how maternal low-protein-diet during pregnancy (LP0.5) alters the offspring's β-cell function and susceptibility to T2D and to identify the mechanistic link between LP0.5 and sensitivity to cellula stress dysregulation in chronic hyperglycemia and hyperlipidemia conditions (glucolipotoxicity). The roles of O-GlcNAc transferase (OGT), a nutrient-sensing protein and a key regulator of cellular stress responses, in LP0.5 β-cell susceptibility to T2D will also be identified. Thus, th central hypothesis to be tested is that LP0.5 predisposes offspring to T2D by regulating OGT levels, which enhances the susceptibility of β-cells to glucolipotoxicity-induced ER stress and cell death. Three specific aims will be carried out to test this hypothesis: 1) Identify the mechanisms of how LP0.5 β-cell susceptibility to glucolipotoxicity; 2) Identify how OGT activity (enhanced O-GlcNAcylation) modulates β-cell susceptibility to glucolipotoxicity-induced ER stress; and 3) Determine the extent to which gain of O-GlcNAcylation during pregnancy rescues the abnormalities induced by LP0.5. Based on preliminary data, the working hypothesis of these specific aims is that LP0.5 predisposes β-cells to increased sensitivity to glucolipotoxicity by enhancing ER stress and cell death responses by regulating OGT activity. This hypothesis will be tested in vivo by subjecting LP0.5 mice to in vivo infusion of glucose and lipid. β-cell functin, molecular markers of ER stress and cell death, and morphology of the ER will be assessed. The working hypothesis that enhancing O-GlcNAcylation during pregnancy will protect the offspring against T2D by inducing long-term gains in β-cell mass and function will further show the importance of OGT in β-cell development and function. Thus, the metabolic profile and β-cell phenotype of LP0.5 offspring exposed to a drug that enhances O-GlcNAcylation during gestation will be assessed in normal and diabetogenic conditions. These studies will fill significant gaps on the roles of OGT in β-cell development and function and the pathogenesis of T2D and the results will have a significant impact on multiple levels. In the short-term, the generated data will identify the molecular mechanisms by which LP0.5 alters β-cell development, impacting sensitivity to cellular stress and the susceptibility to T2D. The long-term objective is that these studies will aid in the development of drugs targeting OGT and dietary approaches to prevent T2D and other chronic diseases.
描述(由申请人提供):2型糖尿病(T2 D)是世界范围内的主要健康问题。识别可改变的风险因素是降低T2 D发病率和相关经济负担的关键。遗传和环境因素都有助于T2 D的发展。妊娠期间的胎儿营养环境是改变发展T2 D风险的主要因素。来自人类和动物模型的研究表明,胎儿生长不良与妊娠期间母体营养不良导致的T2 D发展之间存在强相关性,这是由于胰腺β细胞功能的永久性变化并增加了对T2 D的易感性。本K 01提案的总体研究目标是了解妊娠期间母体低蛋白饮食(LP 0.5)如何改变后代的β细胞功能和对T2 D的易感性,并确定LP 0.5与慢性高血糖症和高脂血症(糖脂毒性)中细胞应激失调敏感性之间的机制联系。还将确定O-GlcNAc转移酶(OGT)(一种营养敏感蛋白和细胞应激反应的关键调节因子)在LP 0.5 β细胞对T2 D易感性中的作用。因此,待检验的中心假设是LP 0.5通过调节OGT水平使后代易患T2 D,这增强了β细胞对糖脂毒性诱导的ER应激和细胞死亡的易感性。将进行三个具体目标来检验该假设:1)确定LP 0.5 β细胞对糖脂毒性的易感性的机制; 2)确定OGT活性(增强的O-GlcNAc酰化)如何调节β细胞对糖脂毒性诱导的ER应激的易感性; 3)确定妊娠期间O-GlcNAc酰化的获得在多大程度上挽救了LP 0.5诱导的异常。基于初步数据,这些特定目标的工作假设是,LP 0.5通过调节OGT活性增强ER应激和细胞死亡反应,使β细胞倾向于对葡萄糖脂毒性的敏感性增加。将通过对LP 0.5小鼠进行葡萄糖和脂质的体内输注来在体内测试该假设。将评估β细胞功能、ER应激和细胞死亡的分子标志物以及ER的形态。妊娠期间增强O-GlcNAc化将通过诱导β细胞质量和功能的长期增加来保护后代免受T2 D的影响,这一工作假设将进一步表明OGT在β细胞发育和功能中的重要性。因此,将在正常和致糖尿病条件下评估妊娠期间暴露于增强O-GlcNAc酰化的药物的LP 0.5后代的代谢特征和β细胞表型。这些研究将填补OGT在β细胞发育和功能中的作用以及T2 D发病机制的重大空白,结果将在多个层面产生重大影响。在短期内,生成的数据将确定LP 0.5改变β细胞发育的分子机制,影响对细胞应激的敏感性和对T2 D的易感性。长期目标是这些研究将有助于开发针对OGT的药物和预防T2 D和其他慢性疾病的饮食方法。

项目成果

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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:
    $ 13.39万
  • 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:
    $ 13.39万
  • 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:
    10625938
  • 财政年份:
    2022
  • 资助金额:
    $ 13.39万
  • 项目类别:
Innate Immune Complement System and Developmental Programming of Functional β Cell Mass
先天免疫补体系统和功能性β细胞群的发育编程
  • 批准号:
    10194574
  • 财政年份:
    2020
  • 资助金额:
    $ 13.39万
  • 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:
    10158468
  • 财政年份:
    2018
  • 资助金额:
    $ 13.39万
  • 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:
    10406255
  • 财政年份:
    2018
  • 资助金额:
    $ 13.39万
  • 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:
    $ 13.39万
  • 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
  • 批准号:
    9387765
  • 财政年份:
    2017
  • 资助金额:
    $ 13.39万
  • 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:
    $ 13.39万
  • 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:
    $ 13.39万
  • 项目类别:

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