Harnessing Cells from Human Milk; Linking Lactation to Metabolism

项目总结： 母乳喂养已被证明可以保护母亲和她们的孩子在以后的生活中免受代谢性疾病的影响。然而， 母亲肥胖和糖尿病独立预测不良的哺乳结果，即使在调整 母乳喂养支持和社会经济因素。这种关系的生理原因尚不清楚。 这项建议旨在确定将哺乳与新陈代谢联系起来的分子机制，长期目标是 制定干预措施以改善肥胖和/或糖尿病妇女的哺乳结果。 对人类哺乳期的调查具有挑战性，因为与获取 处于哺乳期的乳腺组织。人类乳源细胞的单细胞RNA测序表明 这些细胞与驻留在哺乳腺的乳腺上皮细胞(MECs)非常相似。其他内容 细胞分选工作已将乳汁来源的微血管内皮细胞确定为“液态乳腺活检”，这可能被用来回答 关于哺乳生物学的许多悬而未决的问题。 此外，胰岛素信号的微妙平衡是MEC分化和维持所必需的。 乳腺特异的胰岛素受体敲除(MAM-IRKO)阻断MEC的分泌分化，并且 因此会阻碍哺乳。相反，一种活性形式的胰岛素下游的乳房特异性表达 调节剂，AKT，也会导致哺乳失败。为了找出适当的干预方法来改善 在哺乳过程中，了解微血管内皮细胞对胰岛素的反应或抵抗是至关重要的 高胰岛素血症。肥胖妇女和饮食性肥胖小鼠非哺乳期乳腺的研究 提示过早的胰岛素信号可能通过驱动调节失调的腺体而导致这些效应。 发展。本项目的目的是：1.建立孕妇妊娠期糖尿病(GDM)对 微血管内皮细胞前体胰岛素信号转导和乳源性微血管内皮细胞图谱和2.确定胰岛素和其他 代谢激素对巨噬细胞分泌分化和功能的影响。 与BMI匹配的患有和不患有严重妊娠期糖尿病的女性的乳汁来源的微血管内皮细胞将被用来确定 妊娠期糖尿病患者的MEC祖细胞对胰岛素有足够的反应或抵抗，并且差异 MEC人群之间可能解释这些妇女哺乳障碍结果的评估将被评估。在……里面 MEC的体内和体外发育模型将被用来确定胰岛素作用的潜在机制 在MAM-IRKO小鼠中下调的催乳素信号转导。脂肪因子、瘦素和瘦素的作用 脂联素对微血管内皮细胞的发育和功能也将进行研究。 这项提案将为未来研究肥胖和/或糖尿病与人类 哺乳功能障碍。拟议的方法有可能打破世代之间的恶性循环 代谢性疾病。一个由乳房生理学和妊娠期糖尿病专家组成的协作团队将 支持申请者确保这一创新项目的成功。

Project Summary: Breastfeeding has been shown to protect mothers and their children from metabolic disease later in life. However, maternal obesity and diabetes independently predict poor lactation outcomes, even after adjustments for breastfeeding support and socioeconomic factors. The physiological reasons for this relationship remain unclear. This proposal aims to identify the molecular mechanisms linking lactation to metabolism with a long-term goal of developing interventions to improve lactation outcomes in women with obesity and/or diabetes. Investigations of human lactation are challenging due to ethical and practical barriers related to accessing mammary tissue in the lactating state. Single cell RNA sequencing of human milk-derived cells has shown that these cells are remarkably similar to mammary epithelial cells (MECs) resident in the lactating gland. Additional cell sorting efforts have established milk-derived MECs as “liquid breast biopsies” which may be used to answer many outstanding questions regarding lactation biology. Furthermore, a delicate balance of insulin signaling is required for MEC differentiation and maintenance. Mammary specific knockout of the insulin receptor (mam-IRKO) blocks MEC secretory differentiation, and therefore impedes lactation. Conversely, mammary-specific expression of an active form of insulin’s downstream mediator, AKT, also drives lactation failure. In order to identify appropriate interventional approaches to improve lactation performance, it is critical to understand if MECs are responsive or resistant to insulin in the context of hyperinsulinemia. Studies of non-lactating mammary glands in women with obesity and diet-induced obese mice suggest that premature insulin signaling may be responsible for these effects, by driving dysregulated glandular development. The aims of this project are to 1. establish the effect of maternal gestational diabetes (GDM) on MEC progenitor insulin signaling and milk-derived MEC profiles and 2. define the effects of insulin and other metabolic hormones on MEC secretory differentiation and function. Milk-derived MECs of women with and without severe GDM, matching for BMI, will be utilized to determine if MEC progenitors from women with GDM are sufficiently responsive or resistant to insulin, and differences between MEC populations which may explain impaired lactation outcomes in these women will be assessed. In vivo and in vitro models of MEC development will be used to identify the mechanism underlying insulin’s effect on lactogenic prolactin signaling, which is downregulated in mam-IRKO mice. Effects of adipokines leptin and adiponectin on MEC development and function will also be investigated. This proposal will inform future efforts to investigate additional links between obesity and/or diabetes and human lactation dysfunction. The proposed approach has the potential to break a vicious intergenerational cycle of metabolic disease. A collaborative team of experts in mammary physiology and diabetes in pregnancy will support the applicant to ensure success of this innovative project.