Biological mechanisms of control of milk synthesis in mammary glands

奶牛生产的牛奶含有蛋白质、脂肪和碳水化合物，对人类消费者具有重要的营养和功能。这些成分在牛奶中的百分比含量和产量，以及由此产生的牛奶的经济价值，可以根据奶牛的营养状况而有很大差异。加拿大大约有100万头奶牛，乳品行业花费了相当大的努力，通过对奶牛的营养和饲养来管理牛奶的成分。饲料成本总计200万美元/天。本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牛奶的营养和非营养品质是如何决定的理解，以便能够准确预测管理干预的结果。一个将营养物质输送到乳腺并随后转化为牛奶成分的计算机模型将被更新，并测试其预测奶牛对注入葡萄糖和血管扩张剂进入乳腺动脉供应的反应的能力。在培养的乳腺上皮细胞中，我们将描述我们之前确定的对乳糖合成很重要的酶己糖激酶如何移动以适应产奶的需要。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，试图找出生物控制在该途径中的位置。乳糖合成是决定每日奶量的主要因素。最后，将研究乳分泌细胞外的乳前体浓度如何传递给细胞内的蛋白质合成机制。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，操纵牛奶成分的策略，并测试我们对牛奶如何合成的理解。

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.