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。这些成分在牛奶中的百分比含量和产量，以及牛奶的经济价值，可以根据奶牛的营养而变化很大。加拿大的乳制品行业花费了相当大的努力，通过营养和饲养奶牛来管理牛奶的成分，其中大约有100万头。饲料费用共计200万美元/天。本提案的目的是利用计算机建模、细胞培养和肠外营养输注技术，以提高对如何确定牛奶营养和非营养质量的理解，从而可以准确预测管理干预的结果。将更新向乳腺输送营养物质及其随后转化为乳汁成分的计算机模型，并测试其预测奶牛对葡萄糖和血管扩张剂输注至乳腺动脉供应的反应的能力。在培养的乳腺上皮细胞中，我们将描述我们先前已确定为对乳糖合成很重要的酶己糖激酶如何移动以适应牛奶生产的需要。然后，我们将对将细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，以确定生物控制在该途径中的位置。乳糖的合成是决定每天产奶量的主要因素。最后，将研究乳汁分泌细胞外乳汁前体的浓度与内部蛋白质合成机制之间的联系。我们将观察信号通路中事件的时间进程，然后建立一个计算机模型来模拟这些观察结果。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，牛奶成分的操作策略，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.