Gene-environment interaction in islet serotonin metabolism and impacts on maternal glucose homeostasis

胰岛血清素代谢中的基因-环境相互作用及其对母体葡萄糖稳态的影响

• 批准号: 10634224
• 负责人: Martha Susiarjo
• 金额: $ 52.16万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634224
• 关键词: Affect; Agonist; Agreement; Alkaline Phosphatase; Antibodies; Beta Cell; Binding; Biological Availability; Biology; C57BL/6 Mouse; Cell Proliferation; Child; Chronic; Complex; Country; Data; Diabetes Mellitus; Diagnosis; Dietary Factors; Disease; Dose; Endocrine Disruptors; Environmental Exposure; Environmental Risk Factor; Epidemiology; Etiology; Event; Exposure to; Failure; Fetal health; Gene Expression; Genetic; Gestational Diabetes; Glucose Intolerance; Goals; Health; Human; Immunofluorescence Immunologic; Impairment; Insulin; Insulin Resistance; Islets of Langerhans; Knowledge; Ligands; Link; Liquid Chromatography; Mass Spectrum Analysis; Maternal Health; Metabolic; Metabolism; Methods; Mothers; Mus; National Health and Nutrition Examination Survey; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Participant; Phenotype; Physiological; Pilot Projects; Play; Predisposition; Pregnancy; Pregnancy Complications; Pregnant Women; Premature Birth; Premature Infant; Production; Proliferating; Public Health; Publishing; Pyridoxal Phosphate; Receptor Activation; Regulation; Reporting; Research; Resolution; Risk; Risk Factors; Role; Second Pregnancy Trimester; Serotonin; Serum; Signal Transduction; Structure of beta Cell of islet; Testing; Vitamin A; Vitamin B6; Vitamin B6 Metabolism Pathway; Woman; Work; blood glucose regulation; cofactor; dietary; environmental chemical; epidemiology study; epigenome; epigenomics; fasting glucose; gene environment interaction; health of the mother; histone modification; insight; insulin secretion; islet; maternal hyperglycemia; mouse model; obstetrical complication; perfluorooctanoic acid; phosphatase inhibitor; pregnant; prevent; programs; receptor; response; serotonin receptor; transcriptome; transcriptome sequencing; transcriptomics

ABSTRACT Gestational diabetes is characterized by chronic maternal hyperglycemia during pregnancy without a prior diagnosis of diabetes. It is a very common obstetric complication affecting ~10-25% pregnant women globally. Because women with gestational diabetes are more likely to have other pregnancy complications, deliver large for gestational or premature babies, and develop type II diabetes, gestational diabetes poses a serious threat to the health of mother and baby. Although some risk factors have been defined, the underlying mechanisms are complex and the precise etiologies are poorly understood. Recent studies show that pancreatic serotonin signaling plays a critical role in maternal glucose homeostasis. Increased serotonin synthesis in the pancreatic islet is a critical event that promotes beta cell proliferation and increased insulin secretion that are needed to prevent maternal hyperglycemia during pregnancy. Dietary and genetic factors that reduce islet serotonin synthesis are causatively linked to gestational diabetes in mice. Our preliminary studies show that low dose exposure to perfluorooctanoic acid (PFOA) is associated with reduced abundance of serotonin and its critical cofactor vitamin B6 in the pancreas from pregnant C57BL/6 mouse. These results are consistent with epidemiological findings that PFOA exposure in pregnant women is linked to maternal hyperglycemia, insulin resistance, and glucose intolerance. Interestingly, DBA/2J mice exposed to PFOA do not develop gestational diabetes. The C57BL/6 and DBA/2J mice differ in their abilities to metabolize vitamin B6 due to differences in activities of alkaline phosphatase (ALP). These results suggest that environmental exposure-induced gestational diabetes is modulated by genetic background and higher endogenous vitamin B6 level confers a protection. The overall hypothesis is that PFOA exposure in pregnant mice is causatively linked to gestational diabetes through mechanisms that perturb serotonin metabolism in maternal pancreatic islets and the effects are modulated by genetic differences in vitamin B6 bioavailability. We propose to investigate beta cell proliferation and serotonin abundance in control and PFOA-exposed pregnant C57BL/6 mice to determine whether the gestational diabetes is causatively linked to reduced beta cell expansion and reduced insulin secretion. We also wish to investigate whether treatment with an ALP inhibitor in the DBA/2J pregnant mice will reduce vitamin B6 in pancreatic islets and result in loss of protection to gestational diabetes. Finally, to determine how pregnancy and gestational diabetes influence islet programming, we will perform RNA sequencing and Cleavage Under Targets and Tagmentation followed by sequencing to study changes in the transcriptome and epigenome in response to physiological changes and disease. The proposed research will provide knowledge on mechanisms underlying gestational diabetes that benefit public health.

抽象的 妊娠糖尿病的特征是妊娠期间慢性孕妇高血糖没有先验 诊断糖尿病。这是一种非常常见的产科并发症，全球影响约10-25％的孕妇。 因为妊娠糖尿病的女性更有可能患有其他妊娠并发症，因此可以提供大量 对于妊娠或过早的婴儿，并患上II型糖尿病，妊娠糖尿病构成严重威胁 对母亲和婴儿的健康。尽管已经定义了一些危险因素，但基本机制 是复杂的，精确的病因是很少的。最近的研究表明胰5-羟色胺 信号在母体葡萄糖稳态中起着至关重要的作用。胰腺中的5-羟色胺合成增加 胰岛是一个关键事件，可促进β细胞增殖和增加的胰岛素分泌物增加 预防怀孕期间产妇高血糖。减少胰岛羟色胺的饮食和遗传因素 合成与小鼠的妊娠糖尿病有关。我们的初步研究表明低剂量 暴露于全氟辛酸（PFOA）与5-羟色胺的丰度及其关键有关 来自怀孕的C57BL/6小鼠胰腺中的辅因子维生素B6。这些结果与 流行病学发现，孕妇的PFOA暴露与母体高血糖，胰岛素有关 抗性和葡萄糖不耐症。有趣的是，暴露于PFOA的DBA/2J小鼠不会发展妊娠 糖尿病。 C57BL/6和DBA/2J小鼠的代谢能力不同，由于差异 碱性磷酸酶（ALP）的活性。这些结果表明环境暴露引起 妊娠糖尿病是由遗传背景调节的，较高的内源维生素B6水平赋予了A 保护。总体假设是，怀孕小鼠的PFOA暴露与妊娠有关 糖尿病通过孕产妇胰岛中血清素代谢的机制和影响 由维生素B6生物利用度的遗传差异调节。我们建议研究β细胞 对照和PFOA暴露于怀孕的C57BL/6小鼠的增殖和5-羟色胺丰度以确定 妊娠糖尿病是否与减少β细胞扩张和减少胰岛素有关 分泌。我们还希望调查在DBA/2J怀孕小鼠中使用ALP抑制剂治疗是否会 减少胰岛中的维生素B6，并导致妊娠糖尿病的保护损失。最后，到 确定怀孕和妊娠糖尿病如何影响胰岛编程，我们将执行RNA 测序和裂解目标和标记下，然后进行测序研究改变的变化 对生理变化和疾病的响应的转录组和表观基因组。拟议的研究将 提供有关使公共卫生有益于妊娠糖尿病的机制的知识。