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

在美国，只有25%的女性纯母乳喂养六个月。牛奶不足 生产是过早停止母乳喂养的主要原因。在全球，每年有近100万人死于 如果所有母亲都母乳喂养六个月，每年的妇女和儿童都可以得到预防。母性应激应激 婴儿住院或创伤分娩使妇女容易产生不良的母乳喂养结果。这个 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，就像肥胖症一样，哺乳开始 母乳喂养中断导致母乳喂养效果不佳。此外，合成的GC会导致瞬时抑制 牛奶生产。必须确定过多的GCs抑制哺乳的机制，以使低乳量 供应是可以预防或处理的。 体外研究表明，GCs对α-乳清蛋白(LALBA)合成的双相调节是 在应激诱导的哺乳抑制的病理生理学中处于中心地位。LALBA是一种修饰蛋白，需要 乳糖合成和牛奶生产。将使用小鼠乳腺组织块模型来测试 MR和GR与转录信号转导和激活因子异源二聚体的假说 (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及其候选转录调控因子的表达。AIM 2将询问DNA与蛋白质的结合 在Lalba启动子上，MR、GR与磷酸化的STAT3或STAT5结合。这项研究的发现将提供 对GC对牛奶生产的调控缺乏机械性的洞察，并以此为基础 用于制定预防、管理或治疗牛奶供应不足的指导方针。 申请者将在加州大学戴维斯分校出色的环境中与领先的 研究哺乳激素调节的科学家，以及母乳喂养的创始人卡罗琳·钱特里博士 医学界和临床哺乳研究人员。拟议的研究和培训计划将建立 在乳腺分子基因组学方面的研究专长，加强对临床哺乳的了解 和乳房健康，并提供科学交流和行为的技能。总体培训计划与 随着美国国立卫生研究院最近提出的增加安全和有效的知识和研究的建议 为哺乳妇女提供治疗，并将为申请者成为一名独立的内科医生-科学家做好准备 在母乳喂养医学和哺乳生物学方面。

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.