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%的女性在六个月内完全母乳喂养。奶水不足 生产是过早停止母乳喂养的主要原因。在全球范围内， 如果所有母亲都母乳喂养六个月，每年妇女和儿童就可以预防。母体压力 婴儿住院或创伤性分娩使妇女容易出现母乳喂养不良结果。的 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，如发生在肥胖症中， 导致母乳喂养效果不佳。此外，合成的GC引起瞬时抑制， 牛奶生产。过多的GC抑制泌乳的机制必须明确， 供应可以预防或治疗。 体外研究表明，GC对α-乳白蛋白（LALBA）合成的双相调节是 应激诱导泌乳抑制的病理生理学的中心。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 MR和GR与信号转导子和转录激活子异二聚化假说 （STAT-3或-5）来调节Lalba转录。目标1将定义GC浓度随时间对 Lalba及其候选转录调节因子的表达。目的2将询问DNA-蛋白质结合， MR、GR在Lalba启动子处具有磷酸化的STAT 3或STAT 5。这项研究的结果将提供 缺乏对GC调节产奶量的机制性认识， 制定预防、管理或治疗牛奶供应不足的指南。 申请人将在加州大学戴维斯分校的优秀环境中接受Russ Hovey博士的培训， 科学家在哺乳激素调节，和卡罗琳Chantry博士，母乳喂养的创始人， 医学领域和临床哺乳研究者。拟议的研究和培训方案将建立 研究乳腺分子基因组学的专业知识，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。整体培训计划与 美国国立卫生研究院最近建议增加对安全有效的 治疗哺乳期妇女，并将准备申请人的职业生涯作为一个独立的医生，科学家 母乳喂养医学和哺乳生物学。