Biological mechanisms of control of milk synthesis in mammary glands

奶牛生产的牛奶含有对人类消费者具有营养和功能意义的蛋白质、脂肪和碳水化合物。牛奶中这些成分的百分比、含量和产量，以及牛奶的经济价值，可能因奶牛的营养而有很大的不同。加拿大的乳品业花费相当大的努力，通过营养和奶牛饲养来管理牛奶的成分，大约有100万头奶牛。饲料成本总计200万美元/天。这项建议的目的是利用计算机建模、细胞培养和肠外营养输注技术来提高对如何确定牛奶的营养和非营养质量的理解，以便能够准确地预测管理干预的结果。将更新和测试一个将营养物质输送到乳腺并随后将其转化为牛奶成分的计算机模型，以确定其预测奶牛对向乳腺动脉供应中注入葡萄糖和血管扩张剂的反应的能力。在培养的乳腺上皮细胞中，我们将描述己糖激酶酶是如何移动以适应牛奶生产的需要的，我们之前已经确定己糖激酶对乳糖合成非常重要。然后，我们将对将胞外葡萄糖转化为乳糖的多个生化步骤进行全面的测量和分析，试图找出生物控制在该途径中的哪里。乳糖合成是每日奶量的主要决定因素。最后，将研究乳汁分泌细胞外的乳前体浓度传递到乳汁分泌细胞内的蛋白质合成机器的机制。我们将观察信号通路中事件的时间过程，然后建立一个计算机模型来模拟这些观察。我们建立的计算机模型可以用来分析牛奶生产的潜在效率，控制牛奶成分的策略，并测试我们对牛奶是如何合成的理解。

The milk produced by cows contains proteins, fats and carbohydrates of nutritional and functional significance for human consumers. The percentage content and yield of these components in milk, and consequently the economic value of milk, can vary widely according to the nutrition of the cow. The dairy industry in Canada expends considerable effort to manage the composition of milk through nutrition and breeding of dairy cows, of which there are approximately 1 million. Costs of feed total $2 million/day. The purpose of this proposal is to harness the techniques of computer modelling, cell culture and parenteral nutrient infusion to improve understanding of how the nutritive and non-nutritive qualities of cows' milk are determined so that the outcome of management interventions can be predicted with accuracy. A computer model of the delivery of nutrients to the mammary glands and their subsequent conversion into milk components will be updated and tested for its ability to predict responses of cows to infusion of glucose and a vasodilator into the mammary arterial supply. In mammary epithelial cells in culture, we will characterize how the enzyme hexokinase, which we have previously identified as being important for lactose synthesis, is moved around to accommodate needs for milk production. Then we will conduct comprehensive measurement and analysis of the multiple biochemical steps that convert extracellular glucose into lactose in an attempt to pinpoint where the biological control lies in the pathway. Lactose synthesis is the major determinant of daily milk volume. Finally, the mechanism by which the concentration of milk precursors outside the milk secretory cell is communicated to the protein-synthesizing machinery inside will be studied. We will observe the timecourse of events in the signalling pathway and then build a computer model to simulate those observations. The computer models we build can be used to analyze potential efficiencies of milk production, strategies for manipulation of milk composition, and test our understanding of how milk is synthesized.