The role of glucocorticoids in the regulation of alpha-lactalbumin and milk production.

糖皮质激素在调节 α-乳清蛋白和产奶中的作用。

• 批准号: 10485988
• 负责人: Anna Sadovnikova
• 金额: $ 5.14万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2026-04-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485988
• 关键词: Acute; Binding; Binding Sites; Biological Factors; Biology; Birth; Breast; Breast Feeding; Cessation of life; Child; Clinical; Communication; Complex; Corticosterone; DNA-Binding Proteins; Development; Dexamethasone; Dose; Environment; Exclusive Breastfeeding; Foundations; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Guidelines; Health; Heterodimerization; Hormones; Hospitalization; Human Milk; Hydrocortisone; In Vitro; Induction of Apoptosis; Infant; Infant Mortality; Insulin; Knowledge; Lactalbumin; Lactation; Lactose; Maintenance; Mammary gland; Maternal Mortality; Mediating; Medicine; Messenger RNA; Milk; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Molecular; Mothers; Mus; Obesity; Outcome; Pathway interactions; Phase; Phosphorylation; Physicians; Postpartum Period; Prevention Guidelines; Prolactin; Protein Biosynthesis; Proteins; Recommendation; Regulation; Repression; Research; Research Personnel; Rodent; Role; STAT protein; STAT3 gene; Scientist; Site; Stat3 protein; Stat5 protein; Stress; Testing; Therapeutic; Time; Training; Training Programs; Transactivation; Transcriptional Regulation; United States; United States National Institutes of Health; Water Movements; Woman; Work; biological adaptation to stress; career; chromatin immunoprecipitation; effective therapy; hormone regulation; insight; lactogenesis; mRNA Expression; malignant breast neoplasm; mammary epithelium; maternal obesity; maternal stress; milk production; milk supply; pharmacologic; premature; prevent; promoter; protein expression; response; skills; steroid hormone; steroid hormone receptor

Only 25% of women in the United States breastfeed exclusively for six months. Insufficient milk production is a primary cause of premature breastfeeding cessation. Globally, nearly a million annual deaths of women and children each year could be prevented if all mothers breastfed for six months. Maternal stress due to infant hospitalization or traumatic birth predisposes women to poor breastfeeding outcomes. The glucocorticoid (GC) hormone contributes to the stress response by activating the mineralocorticoid (MR) and glucocorticoid receptors (GR). When GC secretion is dysregulated, as occurs in obesity, lactation initiation is disrupted leading to poor breastfeeding outcomes. Moreover, synthetic GCs cause a transient suppression of milk production. The mechanism by which excessive GCs suppress lactation must be defined so that low milk supply can be prevented or treated. In vitro studies suggest that the biphasic regulation of alpha-lactalbumin (LALBA) synthesis by GCs is central to the pathophysiology of stress-induced lactation suppression. LALBA is a modifier protein required for lactose synthesis and milk production. The mouse mammary gland explant model will be used to test the hypothesis that the MR and GR heterodimerize with the Signal Transducer and Activators of Transcription (STAT-3 or -5) to regulate Lalba transcription. Aim 1 will define the effect of GC concentration over time on the expression of Lalba and its candidate transcriptional regulators. Aim 2 will interrogate DNA-protein binding of MR, GR with phosphorylated STAT3 or STAT5 at the Lalba promoter. The findings from this research will provide an absent mechanistic insight into the regulation of milk production by GC and stand to serve as the foundation for the development of guidelines for the prevention, management, or treatment of insufficient milk supply. The applicant will train in the outstanding environment at UC Davis with Dr. Russ Hovey, a leading scientist in the hormonal regulation of lactation, and Dr. Caroline Chantry, a founder of the breastfeeding medicine field and clinical lactation researcher. The proposed research and training program will establish research expertise in the molecular genomics of the mammary gland, strengthen knowledge of clinical lactation and breast health, and provide skills in scientific communication and conduct. The overall training plan aligns with the recent recommendations from the NIH to increase knowledge and research on safe and effective therapies for lactating women and will prepare the applicant for a career as an independent physician-scientist in breastfeeding medicine and lactation biology.

在美国，只有 25% 的女性纯母乳喂养六个月。奶水不足 生产是过早停止母乳喂养的主要原因。全球每年有近百万人死亡 如果所有母亲都进行六个月的母乳喂养，那么每年妇女和儿童都可以得到预防。产妇压力所致 婴儿住院或创伤性分娩容易导致妇女母乳喂养结果不佳。这 糖皮质激素（GC）激素通过激活盐皮质激素（MR）和 糖皮质激素受体（GR）。当 GC 分泌失调时（如肥胖症中发生的情况），泌乳开始 中断导致母乳喂养结果不佳。此外，合成 GC 会导致瞬时抑制 牛奶生产。必须明确过量 GC 抑制泌乳的机制，以便减少泌乳量 供应可以预防或治疗。 体外研究表明 GC 对 α-乳清蛋白 (LALBA) 合成的双相调节 应激引起的泌乳抑制的病理生理学的核心。 LALBA 是一种修饰蛋白 乳糖合成和牛奶生产。小鼠乳腺外植体模型将用于测试 假设 MR 和 GR 与信号转导子和转录激活子形成异二聚体 （STAT-3 或-5）调节 Lalba 转录。目标 1 将定义 GC 浓度随时间的变化对 Lalba 及其候选转录调节因子的表达。目标 2 将探究 DNA 与蛋白质的结合 MR、GR 在 Lalba 启动子处具有磷酸化的 STAT3 或 STAT5。这项研究的结果将提供 对 GC 调节产奶量缺乏机械洞察，并可作为基础 制定预防、管理或治疗牛奶供应不足的指南。 申请者将在加州大学戴维斯分校优越的环境中，跟随著名的 Russ Hovey 博士进行培训。 哺乳期荷尔蒙调节科学家、母乳喂养创始人 Caroline Chantry 博士 医学领域和临床哺乳研究员。拟议的研究和培训计划将建立 乳腺分子基因组学的研究专业知识，加强临床哺乳知识 和乳房健康，并提供科学沟通和行为的技能。整体训练计划一致 NIH 最近建议增加安全有效的知识和研究 针对哺乳期妇女的治疗方法，并将帮助申请人为独立医师科学家的职业生涯做好准备 母乳喂养医学和哺乳生物学。