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: 10441864
• 负责人: Anna Sadovnikova
• 金额: $ 0.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441864
• 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％的妇女只有六个月的母乳喂养。牛奶不足 生产是过早母乳喂养停止的主要原因。在全球范围内，每年将近一百万次死亡 如果所有母亲母乳喂养六个月，则每年都可以预防妇女和儿童。孕产妇应有的应力 婴儿住院或创伤性出生使妇女患有不良的母乳喂养结果。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，如肥胖症所发生的那样，泌乳开始是 破坏导致母乳喂养不良的结果。此外，合成GC会引起短暂抑制 牛奶生产。必须定义过多的GC抑制泌乳的机制，以使低牛奶 供应可以预防或处理。 体外研究表明，GCS的双相调节（LALBA）合成是 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。小鼠乳腺外植模模型将用于测试 假设MR和GR异二聚体与信号换能器和转录激活因子 （Stat -3或-5）调节LALBA转录。 AIM 1将随着时间的流逝定义GC浓度对 Lalba及其候选转录调节剂的表达。 AIM 2将询问DNA-蛋白结合的 LALBA启动子的MR，GR具有磷酸化的STAT3或STAT5。这项研究的发现将提供 缺乏对GC调节牛奶生产的机械洞察力，并成为基础 制定预防，管理或治疗牛奶供应不足的准则。 申请人将在UC Davis的杰出环境中与Russ Hovey博士进行培训，Russ Hovey博士 泌乳激素调节的科学家和母乳喂养的创始人Caroline Chantry博士 医学领域和临床哺乳研究人员。拟议的研究和培训计划将建立 乳腺分子基因组学方面的研究专业知识，增强了临床泌乳知识 和乳房健康，并提供科学交流和行为的技能。整体培训计划保持一致 随着NIH的最新建议，以增加对安全有效的知识和研究 哺乳妇女的疗法，并将为申请人做好准备，成为独立医师科学家的职业 在母乳喂养医学和哺乳生物学中。