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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的妊娠期糖尿病的特点是妊娠期间孕妇慢性高血糖，且没有事先治疗。糖尿病的诊断。这是一种非常常见的产科并发症，影响全球约 10-25% 的孕妇。由于患有妊娠糖尿病的女性更容易出现其他妊娠并发症，因此分娩时应对于妊娠期或早产儿，并发展为II型糖尿病，妊娠期糖尿病构成严重威胁为了妈妈和宝宝的健康。尽管已经定义了一些风险因素，但潜在的机制其复杂性和确切的病因尚不清楚。最近的研究表明，胰腺血清素信号传导在母体葡萄糖稳态中起着至关重要的作用。胰腺中血清素合成增加胰岛是促进 β 细胞增殖和增加胰岛素分泌的关键事件，这是预防孕期母亲高血糖。减少胰岛血清素的饮食和遗传因素合成与小鼠妊娠糖尿病有因果关系。我们的初步研究表明，低剂量接触全氟辛酸（PFOA）与血清素丰度降低有关，其关键怀孕 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表明，孕妇接触 PFOA 与母亲高血糖、胰岛素水平有关抵抗力和葡萄糖不耐受。有趣的是，暴露于 PFOA 的 DBA/2J 小鼠不会出现妊娠期症状。糖尿病。由于维生素 B6 的差异，C57BL/6 和 DBA/2J 小鼠代谢维生素 B6 的能力存在差异。碱性磷酸酶（ALP）的活性。这些结果表明，环境暴露引起的妊娠期糖尿病受遗传背景调节，较高的内源性维生素 B6 水平赋予保护。总体假设是，怀孕小鼠的 PFOA 暴露与妊娠期有因果关系。通过扰乱母体胰岛血清素代谢的机制来预防糖尿病及其影响受维生素 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 暴露的怀孕 C57BL/6 小鼠的增殖和血清素丰度，以确定妊娠期糖尿病是否与β细胞增殖减少和胰岛素减少有关分泌。我们还希望研究在 DBA/2J 怀孕小鼠中使用 ALP 抑制剂治疗是否会有效减少胰岛中的维生素 B6 并导致失去对妊娠糖尿病的保护。最后，为了为了确定妊娠和妊娠糖尿病如何影响胰岛编程，我们将进行 RNA 测序和目标下的切割和标记，然后进行测序以研究转录组和表观基因组响应生理变化和疾病。拟议的研究将提供有关妊娠糖尿病潜在机制的知识，有益于公众健康。