Minerals in Nutrition and Development

营养与发育中的矿物质

• 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
• 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

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 婴儿的健康和发展与母亲的健康固有地联系在一起 和营养的分泌。饮食矿物质，包括金属（Cu，Zn，CA，MN，FE）是必需的营养素 身体功能的各个方面都需要。然而，运输蛋白对于营养滥用和 分泌的定义很差，人体组织或体外模型中的功能数据很少 从正常的人类细胞得出，以阐明转运蛋白的适应性如何以及支持 怀孕和哺乳。必须弥合这个基本差距，以改善儿童的健康状况和 母亲。我们在营养和开发中矿物质（开采）的运输阐明中心（TEC）将 利用我们丰富的科学，临床和心理专业知识，以作为发现的枢纽 床边翻译以及人类金属运输和养分吸收领域的训练。最初的重点 采矿中心将在发育中的肠道和适应母乳和乳房中。怀孕期间 和乳腺的乳腺重塑，使牛奶的合成和分泌能够维持 并养育婴儿。重要的是，来自人乳衍生上皮细胞的转录数据指向关键 金属稳态的角色。但是，鉴于获取人类样本的道德挑战和 建立适合用于传输通量研究的体外模型，对金属转运蛋白的功能理解 缺乏它们在泌乳过程中在营养运输中的更广泛作用。在AIM 1中，我们将解决这个差距 通过在哺乳动物上皮中定义人类的“ transportome”来了解知识 乳腺金属素，以阐明养分如何运输到牛奶中。我们将使用人类体外器官 乳腺功能的模型，以识别同步转运蛋白的功能模块 诱导并离散地本地化以完成跨多金属转运。使用基因编辑技术， 我们将系统地在SLC的可溶性载体家族中进行系统的删除，以脱离甲虫的理解 运输者并揭示了潜在的新作用在牛奶生产和分泌中。在AIM 2中，完整的研究 使用人类的成人和小儿十二指肠和空肠肠to虫将决定金属转运蛋白在 肠道适应性和营养抽象，以支持儿童发育，孕产妇妊娠和哺乳。 我们将询问妊娠和乳酸激素如何改变肠道增殖，转运蛋白 瞄准3的目标是 建立基础设施和基本发现管道，以支持对人类运输商的未来研究。 开采的位置很好，可以作为基础研究和临床研究之间合作的联系，以促进 通过共享知识和资源并在进行研究中，科学界的互动 人类转运蛋白生理学科学领域的谈判，讲习班和半小说，并促进职业 通过为创新项目提供种子资金来发展潜水员早期的职业科学家。