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Harnessing Cells from Human Milk; Linking Lactation to Metabolism

利用人乳细胞；

基本信息

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
项目类别：
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

项目摘要

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.

项目总结: