Placental Hormones and O-GlcNAcylation in Gestational Diabetes

项目总结/摘要 每年，大约有1800万婴儿出生于患有妊娠糖尿病（GDM）的母亲。 虽然糖尿病症状通常在分娩后消退，但母亲和母亲都可能发生持久的并发症。 和儿童，包括胎儿过度生长，2型糖尿病（T2 D），心血管疾病和肥胖症。 虽然在病理学上与2型糖尿病相似，但GDM的快速进展是独特的， 怀孕，可能是由胎盘功能障碍引起的。血糖可利用性增加， 健康怀孕对胎儿的正常发育至关重要。胎盘激素的激增会引发一种状态 轻度胰岛素抵抗，结合β细胞功能障碍，可能导致GDM。目前， GDM的有效治疗是有限的或不安全的。因此，深入了解 GDM的病理生理学对于预防GDM和设计创新的，无毒的， 高效的GDM治疗我们的研究计划旨在调查GDM的发展， 首次研究营养素依赖性O-GlcNAc酰化对胎盘内分泌的作用 功能直接依赖于血浆葡萄糖水平，细胞内O-GlcNAc酰化是一种常见的 动态翻译后修饰影响许多信号通路和疾病。 基于文献和初步数据，我们收集到O-GlcNAc酰化影响经典激素， 分泌（在非妊娠动物中），对于胎盘生理学是关键的，并且损害胰岛素信号传导。 因此，我们假设O-GlcNAc酰化依赖性激素变化部分驱动GDM。一是 将定义O-GlcNAc酰化蛋白在生理性胎盘内分泌中的参与 第二，评估O-GlcNAc失调是否导致GDM。我们希望提出新颖的 胎盘生理和疾病的分子靶点和信号通路及其进展 妊娠代谢性疾病的防治。

PROJECT SUMMARY/ ABSTRACT Every year, about 18 million babies are born from mothers with gestational diabetes mellitus (GDM). While diabetic symptoms usually resolve after delivery, lasting complications can occur for both mother and child, including fetal overgrowth, type 2 diabetes (T2D), cardiovascular diseases, and obesity. While pathologically similar to type 2 diabetes, the rapidity of progression of GDM is unique to pregnancy, and likely arises from placental dysfunction. Increased blood glucose availability in a healthy pregnancy is vital for proper fetal development. A surge of placental hormones initiates a state of mild insulin resistance, which, combined with beta-cell dysfunction, likely causes GDM. Currently, effective treatments for GDM are limited or unsafe. Thus, an in-depth understanding of the pathophysiology of GDM becomes essential to prevent GDM and design innovative, non-toxic, and highly effective GDM treatments. Our research program aims to investigate GDM development by studying for the first time the role of nutrient-dependent O-GlcNAcylation on placental endocrine function. Directly dependent on plasma glucose levels, intracellular O-GlcNAcylation is a common dynamic post-translational modification that impacts numerous signaling pathways and diseases. Based on literature and preliminary data, we gathered that O-GlcNAcylation affects classical hormonal secretion (in non-pregnant animals), is critical for placental physiology, and impairs insulin signaling. Thus, we hypothesize that O-GlcNAcylation-dependent hormonal changes partly drive GDM. First, we will define the involvement of O-GlcNAcylated protein in physiological placenta endocrine secretion and, second, assess whether O-GlcNAc deregulations lead to GDM. We hope to propose novel molecular targets and signaling pathways involved in placental physiology and disease and advance the prevention and treatment of pregnancy metabolic diseases.