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.

总结 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。 和营养分泌。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。然而，对营养吸收和营养代谢至关重要的转运蛋白质 分泌定义不明确，在人体组织或体外模型中缺乏功能数据 从正常的人类细胞中获得，以阐明转运蛋白如何以及如何发生适应性变化，以支持 怀孕和哺乳。必须弥合这一根本性差距，以改善儿童的健康状况， 妈妈们我们的运输阐明中心（TEC）的矿物质营养和发展（MINeD）将 利用我们丰富的科学、临床和指导专业知识，作为发现、实验室到实验室的中心， 床边翻译，以及人体金属转运和营养吸收领域的培训。最初的重点 MINeD中心将位于发育中的肠道和适应母体肠道和乳房。在怀孕期间 和哺乳期，乳腺的急剧重塑使牛奶的合成和分泌得以维持， 滋养婴儿重要的是，来自人类乳源性上皮细胞的转录数据指向了一个关键点， 金属稳态的作用。然而，鉴于获取人体样本的道德挑战， 建立合适的转运通量研究的体外模型，了解金属转运蛋白的功能 并且缺乏它们在乳生成过程中的营养转运中的更广泛的作用。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"转运蛋白组"及其与乳腺癌的关系， 乳腺金属蛋白组，以阐明营养物质是如何被运输到牛奶。我们将使用人类体外类器官 乳腺功能模型，以确定同步转运的功能模块 诱导并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家族溶质载体中的缺失， 转运蛋白和揭示潜在的新作用，在牛奶的生产和分泌。在目标2中，补充研究 使用成人和儿童的十二指肠和空肠类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、母亲怀孕和哺乳。 我们将探讨妊娠激素和催乳激素如何改变肠道增殖、转运蛋白 质膜丰度、脂肪吸收、金属含量和分布。MINeD的目标3是 建立基础设施和基本发现管道，以支持未来对人类运输者的研究。 MINeD能够很好地作为基础和临床研究之间合作的纽带， 通过分享知识和资源以及主办正在进行的研究，促进科学界的互动 讲座，工作坊和研讨会在人类运输生理学的科学领域，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。