Nutritional regulation of endoplasmic reticulum biogenesis in mammary epithelial cells

乳腺上皮细胞内质网生物发生的营养调节

• 批准号: RGPIN-2019-04695
• 负责人: Cant, John
• 金额: $ 3.18万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688757
• 关键词: Nutritional; regulation; endoplasmic; reticulum; biogenesis

There are 945,000 dairy cows in Canada on 10,951 farms and they produce all the fluid milk consumed domestically. The cows' diets are formulated by highly qualified nutritionists employed by feed companies or as independent consultants. One of the goals of ration formulation for dairy cows is to maximize the efficiency of dietary protein capture in milk. Cows typically consume over 4 kg/d of crude protein and secrete approximately 25% of that into milk. The 75% of protein intake that is not captured in milk is excreted as nitrogenous compounds in manure and represents both an environmental and financial loss. Protein capture efficiencies of up to 45% are possible but our understanding of how to consistently obtain such high efficiency is inadequate. The long-term goal of my research program is to improve understanding of the control of milk protein yield in the mammary glands of dairy cows so that responses to dietary manipulation can be predicted quantitatively. We have previously found that milk protein yields cannot be predicted from knowing the concentrations of amino acids in blood. Within minutes of exposure to hormonal and nutritional stimuli, mammary cells up-regulate their rate of mRNA translation into protein. Over several days of nutritional intervention, it appears that factors that control expansion of the intracellular machinery for milk protein secretion during mammary cell differentiation become important regulators of milk protein yield. The main component of this machinery is an organelle called the endoplasmic reticulum (ER). Because ER biogenesis is a new area for investigation, we propose to develop methods to assay ER size and secretory capacity of mammary cells. Once developed, we will use the methods to explore connections between translation activation and secretory differentiation, and to explore effects of growth factors and nutrients on mammary ER biogenesis. While ER biogenesis may be an important contributor to changes in active milk secretory cell numbers, it is not the only contributor, so we will develop a computer simulation model of mammary cell turnover that includes proliferation and apoptosis in addition to differentiation in order to robustly test our hypotheses and identify gaps in knowledge. Findings will be used to design research to improve efficiency of milk protein production. Efficient production is desirable because the protein of milk supplies an ideal amino acid profile for infant growth. In addition, bioactive peptides derived from fermentation or digestion of milk proteins possess functional value in treatment and prevention of symptoms of the human metabolic syndrome including obesity, atherogenesis, arterial hypertension, and type 2 diabetes.**

加拿大有94.5万头奶牛，分布在10951个农场，它们生产国内消费的所有液态奶。奶牛的饲料是由饲料公司聘请的高素质营养学家或独立顾问制定的。奶牛日粮配方的目标之一是最大限度地提高牛奶中蛋白质的捕获效率。奶牛通常每天消耗超过4公斤的粗蛋白质，其中约25%的粗蛋白质分泌到牛奶中。牛奶中摄入的75%的蛋白质未被捕获，以含氮化合物的形式在粪便中排泄，这既是环境损失，也是经济损失。高达45%的蛋白质捕获效率是可能的，但我们对如何持续获得如此高的效率的理解是不够的。我的研究计划的长期目标是提高对奶牛乳腺乳蛋白产量控制的认识，以便定量预测对饮食操纵的反应。我们以前已经发现，牛奶蛋白的产量不能通过知道血液中氨基酸的浓度来预测。在暴露于激素和营养刺激的几分钟内，乳腺细胞上调mRNA转化为蛋白质的速率。经过几天的营养干预，在乳腺细胞分化过程中，控制乳蛋白分泌的细胞内机制扩张的因素似乎成为乳蛋白产量的重要调节因子。这一机制的主要组成部分是称为内质网（ER）的细胞器。由于内质网生物发生是一个新的研究领域，我们建议建立检测乳腺细胞内质网大小和分泌能力的方法。一旦开发成功，我们将利用这些方法探索翻译激活与分泌分化之间的联系，并探索生长因子和营养物质对乳腺内质网生物发生的影响。虽然内质网生物发生可能是活性乳分泌细胞数量变化的重要因素，但它并不是唯一的因素，因此我们将开发一个乳腺细胞更新的计算机模拟模型，包括增殖和凋亡以及分化，以强有力地验证我们的假设并确定知识空白。研究结果将用于设计研究，以提高牛奶蛋白的生产效率。高效的生产是可取的，因为牛奶中的蛋白质为婴儿的生长提供了理想的氨基酸结构。此外，从牛奶蛋白发酵或消化中提取的生物活性肽在治疗和预防人类代谢综合征的症状方面具有功能价值，包括肥胖、动脉粥样硬化、动脉高血压和2型糖尿病