Minerals in Nutrition and Development

营养与发育中的矿物质

基本信息

批准号：
10747115
负责人：
RAJINI RAO
金额：
$ 98.25万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-07 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10747115
关键词：
3-Dimensional Adult Affect Area Award Basic Science Biopsy Breast CCL21 gene Carrier Proteins Caseins Cell membrane Cells Cellular Metabolic Process Child Child Development Child Support Childhood Cholesterol Clinical Clinical Research Collaborations Communities Complement 3d Data Development Disease Duodenum Educational workshop Engineering Epithelial Cells Ethics Faculty Family Fatty acid glycerol esters Female of child bearing age Fostering Funding Future Generations Genes Genetic Transcription Goals Health Homeostasis Hormones Human Human Milk Image Immune response Immunohistochemistry In Vitro Infant Infant Development Infant Health Infrastructure Intestines Ions Knock-out Knowledge Lactation Link Lipids Mammaplasty Mammary gland Mammospheres Maps Mass Spectrum Analysis Maternal Health Mental Health Mentors Metals Milk Minerals Modeling Mothers Names Nutrient Nutritional Requirements Organoids Outcome Physiological Physiology Pilot Projects Play Positioning Attribute Pregnancy Production Proliferating Proteome RNA Regulation Research Resources Role Sampling Scientist Series Small Intestines Spatial Distribution Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Technology Tissues Trace Elements Training Triglycerides Work absorption bench-to-bedside translation career career development data visualization dietary mineral hard metal health of the mother human data human tissue improved in vitro Model infancy innovation instrumentation lactogenesis mammary mammary epithelium metabolic imaging milk production milk secretion nutrient absorption nutrition postnatal development response solute symposium three-dimensional modeling uptake web site

项目摘要

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.

概括婴儿的健康和发育通过吸收与母亲的健康有着内在的联系。膳食矿物质，包括金属（铜、锌、钙、锰、铁）是必需的营养素。然而，转运蛋白对于营养吸收和维持至关重要。分泌的定义不明确，并且缺乏人体组织或体外模型的功能数据来自正常人类细胞，以阐明转运蛋白如何以及发生哪些适应来支持必须弥合这一根本差距，以改善儿童和哺乳期的健康状况。我们的营养与发育矿物质运输阐释中心 (TEC) (MINeD) 将利用我们丰富的科学、临床和指导专业知识，作为发现、实验和指导的中心床边翻译，以及人体金属运输和营养吸收领域的培训是最初的重点。 MINeD 中心将位于怀孕期间发育中的肠道和适应母体肠道和乳房。和哺乳期，乳腺的剧烈重塑使乳汁的合成和分泌得以维持重要的是，来自人乳来源的上皮细胞的转录数据指出了一个关键。然而，考虑到获取人体样本的伦理挑战和建立合适的体外模型进行转运通量研究，对金属转运蛋白的功能性理解并且它们在泌乳过程中的营养运输中缺乏更广泛的作用，在目标 1 中，我们将解决这一差距。通过定义哺乳期乳腺上皮中的人类“运输组”及其与乳腺金属组来阐明营养物质如何输送到乳汁中我们将使用人类体外类器官。乳腺功能模型，用于识别同步转运蛋白的功能模块使用基因编辑技术诱导和离散定位以完成跨上皮金属转运。我们将系统地设计 SLC 溶质载体家族中的缺失，以消除未被充分研究的孤儿转运蛋白并揭示在牛奶生产和分泌中的潜在新作用在目标 2 中，补充研究。使用成人和儿童十二指肠和空肠小肠将确定金属转运蛋白在肠道适应和营养吸收，以支持儿童发育、孕产妇怀孕和哺乳。我们将询问妊娠和泌乳激素如何改变肠道增殖、转运蛋白 MINeD 的目标 3 是质膜丰度、脂肪吸收以及金属含量和分布。建设基础设施和基础发现管道，以支持未来对人类运输工具的研究。 MINeD 处于有利地位，可以作为基础研究和临床研究之间合作的纽带，以促进通过共享知识和资源以及主持正在进行的研究来在科学界进行互动人体转运生理学科学领域的讲座、讲习班和研讨会，并促进职业发展通过为创新项目提供种子资金来培养多样化的早期职业科学家。