Genetics and genomics of human breast milk composition

项目摘要 母乳喂养对婴儿和产妇的健康起着至关重要的作用；然而，母乳的基本成分 牛奶对健康的影响和牛奶成分变化的后果还没有被很好地理解。除了 在一些牛奶成分中，母体遗传学在牛奶组成中的作用在很大程度上是未知的，限制了 可用于梳理乳汁成分变化对婴儿和母亲影响的流行病学工具 健康。因此，加强我们对牛奶成分变异的遗传和基因组基础的理解是 这对于确定母乳喂养与婴儿和产妇健康结果之间的联系机制至关重要。这样的一个 结果是婴儿肠道微生物群，其中母乳喂养是一个主要决定因素，其影响 新生的免疫系统和孩子的长期代谢健康。该提案包含一个 综合分析母乳的分子和细胞组成，对母体的影响 关于这种成分的遗传学，以及牛奶中宿主-微生物群相互作用对婴儿肠道的影响 微生物组。这一结果将为推进牛奶研究提供基础数据，并有助于推动我们的 在生命关键的前1000天，人类的营养知识。三个具体目标将解决这些问题 优先事项：(1)应用单细胞rna-seq在#年的两个时间点评估牛奶的细胞组成 哺乳期，从而描绘了在整个哺乳期和母体乳腺中基因表达的变化 为新生儿提供关键免疫支持的免疫细胞；(2)识别相关的遗传变异 与牛奶中的基因表达(EQTL)和牛奶中细胞类型-eQTL的互作；以及(3)应用多组学数据 整合乳汁基因表达、乳汁微生物组和婴儿肠道微生物组以揭示生物 这些系统的共同变异的潜在途径，并评估母体代谢的影响 在这些道路上保持健康。每个目标都将利用以前从未应用过的尖端基因组学技术 以扩大我们对牛奶组成的遗传和基因组基础的理解。研究 将在明尼苏达大学双子城分校举行，这是一家主要的研究机构，拥有最先进的 基因组学和临床/转化性研究的核心设施。受训人员将接受有关生物方面的培训 乳汁和哺乳，计算生物学，人体研究，以及负责任的研究 流行病学、社区卫生和遗传学系的跨学科赞助团队， 细胞生物学与发育。这一培训计划将使学员获得技能和科学的 基金会开始她的独立学术生涯。

Project Summary Breastfeeding plays a critical role in infant and maternal health; however, the components of milk underlying the health effects of milk and consequences of variation in milk composition are not well understood. Except for a few milk components, the role of maternal genetics in milk composition is largely unknown, limiting the epidemiological tools available to tease apart the effects of variation in milk composition on infant and maternal health. Thus, enhancing our understanding of the genetic and genomic basis of variation in milk composition is critical for identifying the mechanisms linking breastfeeding to infant and maternal health outcomes. One such outcome is the infant gut microbiome, for which breastfeeding is a primary determinant, with implications for the nascent immune system and the child’s long-term metabolic health. This proposal contains a comprehensive analysis of the molecular and cellular composition of breast milk, the effect of maternal genetics on this composition, and the impact of host-microbiome interactions in milk on the infant gut microbiome. The results will provide foundational data for advancing milk research and help advance our knowledge of human nutrition during the critical first 1000 days of life. Three specific aims will address these priorities by (1) applying single cell RNA-seq to assess the cellular composition of milk at two time points in lactation, thus profiling changes in gene expression in the mammary gland across lactation and the maternal immune cells that provide critical immune support to the neonate; (2) identifying genetic variants associated with gene expression in milk (eQTLs) and cell type-eQTL interactions in milk; and (3) applying multi-omic data integration to milk gene expression, the milk microbiome, and infant gut microbiome to uncover the biological pathways underlying shared variation across these systems, and to assess the impact of maternal metabolic health on these pathways. Each Aim will leverage cutting edge genomics techniques never previously applied to human milk to expand our understanding of the genetic and genomic basis of milk composition. Research will take place at the University of Minnesota – Twin Cities, a major research institution, with state-of-the-art core facilities for genomics and clinical/translational research. The trainee will receive training in the biology of milk and lactation, computational biology, human subjects research, and responsible conduct of research from an interdisciplinary sponsorship team in the departments of Epidemiology & Community Health and Genetics, Cell Biology and Development. This training plan will result in the trainee acquiring the skills and a scientific foundation to launch her independent academic career.