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
• 负责人: Emilyn Alejandro
• 金额: $ 13.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8804376
• 关键词: Accounting; Adult; Animal Model; Animals; Apoptosis; Automobile Driving; Beta Cell; Birth; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cellular Stress; Cellular Stress Response; Chronic; Chronic Disease; Data; Development; Diabetes Mellitus; Diet; Disease; Drug Targeting; Economic Burden; Environment; Environmental Risk Factor; Epidemiology; Exhibits; Fatty acid glycerol esters; Fetal Growth; Fetal Growth Retardation; Fetus; Foundations; Functional disorder; Funding; Future; Genetic; Glucosamine; Glucose; Glucose Intolerance; Goals; Growth; Growth and Development function; Health; Human; Hyperglycemia; Hyperlipidemia; In Vitro; Incidence; Infusion procedures; Link; Lipids; Malnutrition; Metabolic; Modeling; Molecular; Morphology; Mus; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; O-GlcNAc transferase; Pancreas; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Post-Translational Protein Processing; Predisposition; Pregnancy; Protein-Restricted Diet; Proteins; Public Health; Rattus; Research; Research Training; Risk; Risk Factors; Role; Stress; Testing; United States National Institutes of Health; Work; arm; base; biological adaptation to stress; cell type; detection of nutrient; fetal; genetic variant; human FRAP1 protein; impaired glucose tolerance; improved; in vivo; inhibitor/antagonist; insulin secretion; islet; modifiable risk; molecular marker; novel; offspring; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; pregnant; prevent; programs; research study; response; response to injury; stressor

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 (T2D) 是世界范围内的一个主要健康问题。识别可改变的风险因素是降低 T2D 发病率和相关经济负担的关键。遗传和环境因素都会导致 T2D 的发生。怀孕期间胎儿的营养环境是改变患 T2D 风险的主要因素。人类和动物模型的研究表明，由于怀孕期间母亲营养不良，胎儿生长不良与 2 型糖尿病的发生之间存在密切关联，这是由于胰腺 β 细胞功能的永久性变化造成的，并增加了对 2 型糖尿病的易感性。该 K01 提案的总体研究目标是了解母亲怀孕期间的低蛋白饮食 (LP0.5) 如何改变后代的 β 细胞功能和对 T2D 的易感性，并确定 LP0.5 与慢性高血糖和高脂血症条件下细胞应激失调的敏感性（糖脂毒性）之间的机制联系。 O-GlcNAc 转移酶 (OGT) 是一种营养感应蛋白，也是细胞应激反应的关键调节因子，在 LP0.5 β 细胞对 T2D 易感性中的作用也将得到确定。因此，要测试的中心假设是，LP0.5 通过调节 OGT 水平使后代易患 T2D，从而增强 β 细胞对糖脂毒性诱导的 ER 应激和细胞死亡的敏感性。将通过三个具体目标来检验这一假设：1）确定 LP0.5 β 细胞对糖脂毒性敏感性的机制； 2) 确定 OGT 活性（增强的 O-GlcNAcylation）如何调节 β 细胞对糖脂毒性诱导的 ER 应激的敏感性； 3) 确定妊娠期间O-GlcNAc糖基化的增加在多大程度上挽救了LP0.5引起的异常。根据初步数据，这些具体目标的工作假设是，LP0.5 通过调节 OGT 活性增强 ER 应激和细胞死亡反应，从而使 β 细胞对糖脂毒性敏感性增加。该假设将通过对 LP0.5 小鼠进行体内葡萄糖和脂质输注来进行体内测试。将评估 β 细胞功能、内质网应激和细胞死亡的分子标记以及内质网的形态。妊娠期间增强 O-GlcNAc 酰化将通过诱导 β 细胞质量和功能的长期增加来保护后代免受 T2D 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，将在正常和糖尿病条件下评估妊娠期间暴露于增强 O-GlcNAcNAc 的药物的 LP0.5 后代的代谢特征和 β 细胞表型。这些研究将填补OGT在β细胞发育和功能以及T2D发病机制中的作用的重大空白，其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 LP0.5 改变 β 细胞发育、影响细胞应激敏感性和 T2D 易感性的分子机制。长期目标是，这些研究将有助于开发针对 OGT 的药物和预防 T2D 和其他慢性疾病的饮食方法。