Harnessing Cells from Human Milk; Linking Lactation to Metabolism

利用人乳细胞；

• 批准号: 10348599
• 负责人: Jayne Frances Martin Carli
• 金额: $ 10.56万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348599
• 关键词: Affect; Animal Model; Apoptosis; Area; Automobile Driving; Biology; Body mass index; Breast Epithelial Cells; Breast Feeding; Breast biopsy; Cell Differentiation process; Cell Maintenance; Cell Separation; Cell physiology; Cells; Child; Data; Development; Diabetes Mellitus; Ensure; Equilibrium; Ethics; FRAP1 gene; Failure; Fasting; Flow Cytometry; Functional disorder; Future; Generations; Gestational Diabetes; Gland; Goals; Health; High Fat Diet; Hormones; Human; Human Milk; Human Subject Research; Hyperinsulinism; INSR gene; Immune; Impairment; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Investigation; Knock-out; Lactation; Leptin; Life; Link; Liquid substance; Mammary gland; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic hormone; Metabolism; Milk; Modeling; Molecular; Mothers; Mus; Myoepithelial cell; Obese Mice; Obesity; Outcome; Pathway interactions; Performance; Phase; Phosphorylation; Physiological; Physiology; Play; Population; Postpartum Period; Pregnancy; Pregnancy in Diabetics; Prolactin; Proto-Oncogene Proteins c-akt; Recording of previous events; Research; Resistance; Risk; Role; Secretory Cell; Signal Transduction; Socioeconomic Factors; Study models; Tissues; Training; Woman; Work; adipokines; adiponectin; base; cardiometabolism; diet-induced obesity; epidemiological model; epithelial stem cell; human RNA sequencing; improved; in vitro Model; in vivo; innovation; insulin sensitivity; insulin signaling; intergenerational; knock-down; lactation period; lactogenesis; mammary; mammary epithelium; maternal diabetes; maternal obesity; milk fat; milk production; milk supply; mouse model; premature; progenitor; programs; protein activation; single-cell RNA sequencing; success; transcriptome sequencing

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.

项目概要： 母乳喂养已被证明可以保护母亲及其孩子在以后的生活中免受代谢疾病的影响。然而， 产妇肥胖和糖尿病独立预测不良的哺乳结果，即使在调整后 母乳喂养支持和社会经济因素。这种关系的生理原因仍不清楚。 该提案旨在确定将哺乳与代谢联系起来的分子机制，其长期目标是 制定干预措施以改善肥胖和/或糖尿病女性的哺乳结果。 由于与获取相关的伦理和实际障碍，对人类哺乳的研究具有挑战性 乳腺组织处于哺乳状态。人乳来源细胞的单细胞 RNA 测序表明 这些细胞与泌乳腺中的乳腺上皮细胞（MEC）非常相似。额外的 细胞分选工作已将乳源性 MEC 建立为“液体乳腺活检”，可用于回答 有关哺乳生物学的许多悬而未决的问题。 此外，MEC 的分化和维持需要胰岛素信号传导的微妙平衡。 乳腺特异性敲除胰岛素受体 (mam-IRKO) 可阻断 MEC 分泌分化，并且 因此会阻碍泌乳。相反，胰岛素下游活性形式的乳腺特异性表达 调节因子 AKT 也会导致泌乳失败。为了确定适当的干预方法来改善 泌乳性能，了解 MEC 在以下情况下对胰岛素是否有反应或耐药至关重要 高胰岛素血症。肥胖女性和饮食诱导的肥胖小鼠的非泌乳乳腺研究 表明过早的胰岛素信号传导可能通过驱动失调的腺体而导致这些影响 发展。该项目的目的是 1. 确定孕产妇妊娠期糖尿病 (GDM) 对 2. MEC 祖细胞胰岛素信号传导和乳源性 MEC 图谱以及定义胰岛素和其他药物的影响 代谢激素对 MEC 分泌分化和功能的影响。 患有和不患有严重 GDM 的女性的乳汁 MEC 与 BMI 相匹配，将用于确定是否 GDM 女性的 MEC 祖细胞对胰岛素有足够的反应或抵抗，并且存在差异 将评估 MEC 人群之间的差异，这可能解释这些妇女的哺乳结果受损。在 MEC 发育的体内和体外模型将用于确定胰岛素作用的机制 影响泌乳素催乳素信号，该信号在 mam-IRKO 小鼠中下调。脂肪因子瘦素和的作用 脂联素对 MEC 发育和功能的影响也将得到研究。 该提案将为未来研究肥胖和/或糖尿病与人类之间的其他联系提供信息。 泌乳功能障碍。所提出的方法有可能打破代际恶性循环 代谢性疾病。由乳腺生理学和妊娠期糖尿病专家组成的协作团队将 支持申请人以确保该创新项目的成功。