Harnessing Cells from Human Milk; Linking Lactation to Metabolism

利用人乳细胞；

• 批准号: 10670056
• 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/10670056
• 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; Exclusion; FRAP1 gene; Failure; Fasting; Flow Cytometry; Functional disorder; Future; Generations; Gestational Diabetes; Gland; Goals; 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; 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; Technology; Tissues; Training; Woman; Work; adipokines; adiponectin; cardiometabolism; diet-induced obesity; epidemiological model; epithelial stem cell; health of the mother; human RNA sequencing; improved; in vitro Model; in vivo; innovation; insulin secretion; insulin signaling; intergenerational; knock-down; lactation period; lactogenesis; mammary; maternal diabetes; maternal obesity; milk fat globule; 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.

项目摘要： 母乳喂养已被证明可以保护母亲及其子女免受后期的代谢疾病。然而， 孕产妇肥胖和糖尿病独立预测泌乳结果不良，即使在调整之后 母乳喂养支持和社会经济因素。这种关系的物理原因尚不清楚。 该提案旨在确定将泌乳与代谢联系起来的分子机制与长期目标 开发干预措施以改善肥胖和/或糖尿病女性的泌乳结局。 由于与进入的道德和实用障碍，对人类泌乳的调查受到挑战 哺乳动物组织处于泌乳状态。人奶衍生细胞的单细胞RNA测序表明 这些细胞与哺乳腺中的乳腺上皮细胞（MEC）非常相似。额外的 细胞分类工作已将牛奶来源的MEC确定为“液体乳房活检”，可用于回答 有关哺乳生物学的许多杰出问题。 此外，MEC分化和维护需要微妙的胰岛素信号传导平衡。 胰岛素受体（MAM-IRKO）的乳腺特异性敲除阻止MEC秘书分化，并且 因此阻碍了泌乳。相反，胰岛素下游的活性形式的乳腺特异性表达 介体（AKT）也会驱动泌乳失败。为了确定适当的介入方法以改进 哺乳性能，重要的是要了解MEC在 高胰岛素血症。肥胖和饮食诱发的肥胖小鼠的女性中非乳腺乳腺的研究 表明通过驱动失调的腺体，过早的胰岛素信号可能是这些影响的原因 发展。该项目的目的是1。建立母体妊娠糖尿病（GDM）对 MEC祖细胞胰岛素信号传导和牛奶来源的MEC谱以及2。定义胰岛素和其他的影响 关于MEC秘书分化和功能的代谢训练。 有或没有严重GDM的女性的牛奶衍生的MEC（与BMI相匹配）将被用来确定是否是否 来自GDM女性的MEC祖细胞对胰岛素有足够的反应或抗性，差异 在可能解释这些妇女泌乳结果受损的MEC人群之间，将评估。在 体内和MEC开发的体外模型将用于识别胰岛素作用的基础机制 在MAM-IRKO小鼠中下调的乳酸催乳素信号传导上。脂肪因子瘦素和 脂联素在MEC开发和功能方面也将进行研究。 该提案将为未来的努力提供研究，以调查肥胖与/或糖尿病与人类之间的其他联系 哺乳功能障碍。提出的方法有可能打破恶性的代际周期 代谢疾病。由乳腺生理学和糖尿病专家组成的合作团队将 支持申请人确保这个创新项目的成功。