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Molecular Determinants of Lactation Success

哺乳成功的分子决定因素

基本信息

批准号：
10442747
负责人：
James Lewis McManaman
金额：
$ 38.1万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442747
关键词：
Academy Affect American Anesthesia procedures Animal Model Apical Apoptosis Bacterial Infections Binding Biochemical Biological Biological Assay Birth Breast Feeding C-terminal Calories Capsid Proteins Cell Culture Techniques Cell membrane Centers for Disease Control and Prevention (U.S.)Child Childhood Complex Data Docking Eicosanoids Electron Microscopy Elements Enzymes Essential Fatty Acids Exclusive Breastfeeding Failure Fat-Soluble Vitamin Fatty acid glycerol esters Fluorescence Microscopy Food Genetic Goals Golgi Apparatus Growth Growth and Development function Health Hormonal Hormones Human Human Milk Impairment Individual Infant Infection Integral Membrane Protein Knockout Mice Knowledge Laboratories Lactation Link Lipids Liquid substance Mammals Mammary gland Mediating Membrane Milk Modeling Molecular Morbidity - disease rate Mothers Mus Nature Neonatal Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Nutrient Nutritional Obesity Overweight Oxidation-Reduction Oxytocin Pediatrics Performance Pharmacology Physiological Play Premature Birth Process Production Prolactin Property Proteins Publishing Recommendation Regulation Resolution Risk Role Scaffolding Protein Secretory Vesicles Signaling Molecule Source Stress Structure Tertiary Protein Structure Testing Time Tissues Transgenic Mice Transgenic Organisms Transport Process United States Virus Diseases Woman Work World Health Organization XDH gene apical membrane butyrophilin cognitive development comparative defined contribution high resolution imaging human model imaging approach in vitro Model innovation lactogenesis mammary maternal diabetes maternal obesity membrane synthesis microscopic imaging milk fat globule milk production milk removal milk secretion mouse genetics mouse model neonatal period neonate novel nutrition obesity in children perilipin postnatal postnatal period prevent response success tool trafficking vesicle transport

项目摘要

Milk is a complex fluid capable of sustaining the total nutrition of the human infant for 6 months or longer, as well as providing protection against infection and common childhood illnesses during the critical early postnatal period. Milk lipids provide the majority of the calories required for neonatal growth, in addition to being the primary mechanism for transferring fat-soluble vitamins to infants and the source of essential fatty acids needed for neonatal membrane synthesis and the synthesis of eicosanoids and other bioactive lipid signalling molecules. To meet caloric and nutritional demands of newborns, a unique apocrine mechanism evolved in mammals to efficiently secrete large quantities of lipid into milk. Evidence from humans and animal models suggest that apocrine lipid secretion is also important for initiating and sustaining lactation, and that interference with this process increases the risk of lactation failure. Work from our laboratories indicates that apocrine lipid secretion involves three mechanistically distinct steps: (1) formation of specialized “docking” contacts between CLD and the apical plasma membrane (APM); (2) membrane envelopment of docked CLD, driven in part by Golgi derived secretory vesicles; and (3) release of membrane enveloped CLD into the luminal space as trilaminar membrane coated structures, referred to as milk fat globules (MFG), by an apocrine scission process. We previously identified interactions between butyrophilin (Btn), a mammary gland specific transmembrane protein, the cytoplasmic redox enzyme, xanthine oxidoreductase (XOR), and the CLD coat protein, perilipin-2 (Plin2) as important for apocrine lipid secretion in mice. Importantly, we have demonstrated that genetic deletion of either of these proteins interferes with CLD secretion, and impairs or prevents lactation. The goals of this proposal are: (1) to investigate the mechanism of apocrine lipid secretion and test the hypothesis that prolactin and oxytocin independently regulate discrete steps of this process; (2) define how apocrine lipid secretion affects apical membrane properties, secretory vesicle trafficking, lactogenesis and lactation success; and (3) to define critical molecular determinants of interactions between XOR, Btn and Plin2 that mediate apocrine lipid secretion. The proposed studies take advantage of novel XOR, Btn and Plin2 knockout mouse models developed in our laboratories, quantitative high resolution imaging, and innovative physiological and biochemical analyses and cell culture models of apocrine lipid secretion to accomplish these goals.

牛奶是一种复杂的液体，能够维持人类婴儿6个月或更长时间的全部营养，如并在关键的出生后早期提供预防感染和常见儿童疾病的保护句号。乳脂提供了新生儿生长所需的大部分卡路里，除了是脂溶维生素向婴儿转运的主要机制及必需脂肪酸的来源新生儿膜合成和二十烷类化合物及其他生物活性脂质信号的合成所需分子。为了满足新生儿的热量和营养需求，一种独特的顶分泌机制在哺乳动物能够有效地将大量脂肪分泌到牛奶中。来自人类和动物模型的证据提示顶分泌脂的分泌对开始和维持哺乳也很重要，而且对这一过程的干预增加了哺乳失败的风险。我们实验室的研究表明顶分泌脂分泌包括三个机械上截然不同的步骤：(1)形成专门的“对接”。 CLD与根尖质膜(APM)之间的接触；(2)对接的CLD的膜包被，部分由高尔基体产生的分泌囊泡驱动；以及(3)包膜的CLD释放到腔间隙作为三层膜覆盖的结构，被顶分泌称为乳脂球(MFG) 裂解过程。我们以前发现了乳腺特异性的丁咯菲林(Btn)之间的相互作用跨膜蛋白、细胞质氧化还原酶、黄嘌呤氧化还原酶(XOR)和CLD外壳蛋白质，Perilipin-2(Plin2)对小鼠的大汗腺脂肪分泌具有重要作用。重要的是，我们已经证明了这两种蛋白质中的任何一种的基因缺失都会干扰CLD的分泌，并损害或阻止哺乳。该方案的目的是：(1)研究大汗腺分泌脂肪的机制，并测试假设催乳素和催产素独立地调节这一过程的离散步骤；(2)定义如何顶分泌脂分泌影响顶膜性质、分泌泡运输、乳汁生成和哺乳成功；以及(3)确定XOR、Btn和Plin2之间相互作用的关键分子决定因素调节大汗腺脂肪分泌的物质。建议的研究利用了新的XOR、Btn和Plin2 我们实验室开发的基因敲除小鼠模型、定量高分辨率成像和创新大汗腺脂肪分泌的生理生化分析和细胞培养模型目标。