Minerals in Nutrition and Development

摘要 婴儿的健康和发育与母亲的健康内在地联系在一起，通过吸收 和营养物质的分泌。膳食矿物质，包括金属(铜、锌、钙、锰、铁)是必需的营养素。 生理功能的各个方面都需要的。然而，对养分吸收和运输至关重要的运输蛋白 分泌物的定义不明确，在人体组织或体外模型中缺乏功能数据 从正常人类细胞中提取，以阐明转运蛋白中的适应如何以及发生什么来支持 怀孕和哺乳。必须弥合这一根本差距，以改善儿童和 母亲们。我们的营养和发展中的矿物运输澄清中心(TEC)将 充分利用我们丰富的科学、临床和指导专业知识，作为从工作台到工作台的发现中心 床边翻译，以及人体金属运输和营养摄取领域的培训。最初的重点是 开采的中心将位于发育中的肠道和适应母体肠道和乳房的位置。在怀孕期间 和哺乳期，乳腺的剧烈重塑使乳汁的合成和分泌得以维持 并滋养婴儿。重要的是，来自人类乳汁来源的上皮细胞的转录数据指向了一个关键 金属动态平衡的作用。然而，考虑到获取人类样本和 建立适用于转运通量研究的体外模型，了解金属转运体的功能 而且它们在乳汁发生过程中营养物质运输方面的更广泛作用是缺乏的。在目标1中，我们将在 通过定义人类乳房上皮中的‘转运组’以及它如何与 乳房金属组阐明营养物质是如何输送到牛奶中的。我们将使用人类体外有机化合物 乳腺功能模型以识别同步的转运体功能模块 诱导和离散定位以完成跨上皮金属转运。利用基因编辑技术， 我们将系统地设计SLC溶质载体家族中的缺失，以使正在研究的人去孤儿 并揭示了在牛奶生产和分泌中潜在的新作用。在目标2中，补充研究 使用成人和儿童十二指肠和空肠肠样将确定金属转运体在 肠道适应和营养吸收，以支持儿童发育、母亲怀孕和哺乳。 我们将询问妊娠激素和乳源激素如何改变肠道增殖、转运蛋白 质膜丰度、脂肪吸收、金属含量及分布。地雷的目标3是 建立基础设施和基础发现管道，以支持未来对人类运输器的研究。 MINE处于有利地位，可以作为基础研究和临床研究之间的合作纽带，以促进 通过共享知识和资源以及主持正在进行的研究来实现科学界的互动 人类运输生理学科学领域的讲座、讲习班和研讨会，并促进职业生涯 通过为创新项目提供种子资金，培养多样化的早期职业科学家。

SUMMARY The health and development of the infant is inherently linked to the health of the mother through the absorption and secretion of nutrients. Dietary minerals, including metals (Cu, Zn, Ca, Mn, Fe) are essential nutrients required for all aspects of physiological function. Yet the transport proteins critical for nutrient absorption and secretion are poorly defined and there is a paucity of functional data in human tissues or in vitro models derived from normal human cells to elucidate how and what adaptations in transporters occur to support pregnancy and lactation. This fundamental gap must be bridged to improve health outcomes for children and mothers. Our Transport Elucidation Center (TEC) on Minerals In Nutrition and Development (MINeD) will capitalize on our rich scientific, clinical, and mentoring expertise to serve as a hub for discovery, bench-to- bedside translation, and training in the area of human metal transport and nutrient uptake. The initial focus of the MINeD center will be in the developing gut and adapting maternal intestine and breast. During pregnancy and lactation, drastic remodeling of the mammary gland enables the synthesis and secretion of milk to sustain and nourish the infant. Importantly, transcriptional data from human milk-derived epithelial cells point to a key role for metal homeostasis. However, given the ethical challenges of acquiring human samples and establishing suitable in vitro models for transport flux studies, a functional understanding of metal transporters and their broader role in nutrient transport during lactogenesis is lacking. In Aim 1, we will address this gap in knowledge by defining the human ‘transportome’ in lactating mammary epithelium and how it relates to the mammary metallome to elucidate how nutrients are transported into milk. We will use human in vitro organoid models of mammary gland function to identify functional modules of transporters that are synchronously induced and discretely localized to accomplish transepithelial metal transport. Using gene-editing technology, we will systematically engineer deletions in the SLC family of solute carriers to de-orphanize understudied transporters and reveal potential new roles in milk production and secretion. In Aim 2, complementary studies using human adult and pediatric duodenal and jejunal enteroids will determine the role of metal transporters in intestinal adaptation and nutrient absorption to support child development, maternal pregnancy and lactation. We will ask how pregnancy- and lactogenic hormones change intestinal proliferation, transporter protein abundance at the plasma membrane, fat absorption, and metal content and distribution. Aim 3 of MINeD is to build the infrastructure and fundamental discovery pipeline to support future studies on human transporters. MINeD is well positioned to serve as a nexus for collaborations between basic and clinical research, to foster interactions in the scientific community by sharing knowledge and resources and hosting research-in-progress talks, workshops and seminars in the scientific areas of human transporter physiology, and to promote career development of diverse early career scientists by providing seed funding for innovative projects.