Placental Hormones and O-GlcNAcylation in Gestational Diabetes

妊娠糖尿病中的胎盘激素和 O-GlcNAc 酰化

• 批准号: 10363426
• 负责人: Stephanie Olivier-Van Stichelen
• 金额: $ 36.42万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-26 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363426
• 关键词: Affect; Animals; Beta Cell; Biological Markers; Blood Glucose; Brain; Cardiovascular Diseases; Cells; Child; Clinical; Complications of Diabetes Mellitus; Cytoplasmic Protein; Data; Development; Diabetes Mellitus; Diet; Disease; Endocrine; Enzymes; Fetal Development; Fetal Macrosomia; Functional disorder; Gestational Diabetes; Glucose; Grant; Health; Hepatocyte; Hormonal; Hormonal Change; Hormone secretion; Human; Impairment; Infant; Insulin Resistance; Knowledge; Lead; Literature; Location; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Measures; Metabolic Diseases; Mitochondrial Proteins; Modification; Molecular; Molecular Profiling; Molecular Target; Mothers; Mus; National Institute of Child Health and Human Development; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Proteins; Nutrient; Obesity; Outcome Study; Pathologic; Phase; Physiological; Physiology; Pituitary Gland; Pituitary Hormones; Placenta; Placental Hormones; Plasma; Post-Translational Protein Processing; Pregnancy; Prevention; Proteins; Research; Role; Serine; Signal Pathway; Signal Transduction; Somatotropin; Symptoms; Testing; Threonine; Time; Treatment Protocols; base; design; detection of nutrient; diabetic; disorder prevention; effective therapy; healthy pregnancy; improved; in vivo; innovation; insulin secretion; insulin signaling; novel; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; prevent; programs; response; trophoblast

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.

项目摘要/摘要 每年约有1800万名婴儿由患有妊娠期糖尿病(GDM)的母亲出生。 虽然糖尿病症状通常在分娩后就会消失，但两位母亲都可能出现持久的并发症 和儿童，包括胎儿过度生长、2型糖尿病(T2D)、心血管疾病和肥胖。 虽然在病理上与2型糖尿病相似，但妊娠期糖尿病的进展速度是独一无二的 妊娠，可能是由胎盘功能障碍引起的。提高血糖可利用性 健康的怀孕对胎儿的正常发育至关重要。胎盘荷尔蒙的激增引发一种状态 轻度胰岛素抵抗，再加上β细胞功能障碍，很可能会导致妊娠期糖尿病。目前， 对妊娠期糖尿病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、无毒和 高效的妊娠期糖尿病治疗。我们的研究计划旨在通过以下方式调查GDM的发展 营养依赖性O-GlcN酰化对胎盘内分泌作用的首次研究 功能。直接依赖于血糖水平，细胞内O-GlcN酰化是一种常见的 动态的翻译后修饰，影响许多信号通路和疾病。 根据文献和初步数据，我们推测O-GlcN酰化影响经典激素 分泌(在非怀孕动物中)对胎盘生理至关重要，并损害胰岛素信号。 因此，我们假设O-GlcN酰化依赖的激素变化部分驱动了GDM。首先，我们 将确定O-GlcNacylated蛋白参与胎盘生理性内分泌分泌 第二，评估O-GlcNAc放松管制是否会导致GDM。我们希望提出小说 涉及胎盘生理和疾病的分子靶点和信号通路及其研究进展 孕期代谢性疾病的防治。