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: 10263150
• 负责人: Anna Sadovnikova
• 金额: $ 4.09万
• 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/10263150
• 关键词: Acute; Apoptosis; 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; 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; Pharmacology; Physicians; Postpartum Period; Prevention Guidelines; Prolactin; Protein Biosynthesis; Proteins; Recommendation; Regulation; Repression; Research; Research Personnel; Research Training; 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; dimer; effective therapy; hormone regulation; insight; lactogenesis; mRNA Expression; malignant breast neoplasm; mammary epithelium; maternal obesity; maternal stress; milk production; milk supply; 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。足够的牛奶