Physiological roles of System A amino acid transporter in fetal growth and development

每100个婴儿中就有3个出生时身材矮小。与正常大小的婴儿相比，小婴儿的储备和承受分娩压力的能力更弱。他们在生命的最初几天死亡和生病的风险更高，在以后的生活中也更容易患上包括糖尿病、高血压和心脏病在内的疾病。因此，胎儿生长受限是一个主要的健康问题。为什么婴儿不能在子宫内达到他们的生长潜力，以及它是如何发生的，在大多数情况下都不清楚。我们正在研究胎儿受限是如何发生的。我们认为答案在于控制婴儿某些器官生长的基因。胎盘是一个特别重要的器官，它为婴儿提供所需的母体营养和氧气。我们认为，位于胎盘细胞膜上的蛋白质，专门负责营养物质在胎盘中的运输，在为生长提供营养物质方面是重要的。我们预测，这些蛋白质数量或活性的减少将意味着婴儿营养不足，无法正常生长。我们计划通过小鼠模型来验证我们的假设，由于氨基酸系统A转运蛋白的去除，幼崽出生时很小。我们计划准确地测量这些动物的营养物质在胎盘中的转移情况，肝脏、大脑和胎盘等器官的处理情况，以及这些小鼠在出生后不久和以后的生活中会患上什么疾病。这些实验将为胎儿发育受限的发生以及氨基酸转运体在发育和疾病中的作用提供重要信息。由于转运蛋白经常被用作药物靶点或递送系统，我们的工作也可以用于诊断和治疗。

Three babies, in every 100, are born small. Small babies have less reserve and ability to withstand the stress of labour than normal-sized babies. They are at a higher risk of death and illness in the first few days of life and also of developing diseases in later life including diabetes, high blood pressure and heart disease. Fetal growth restriction is therefore a major health problem. Why babies fail to reach their growth potential in the womb and indeed how it happens is unclear for most cases. We are studying how fetal restriction occurs. We think that the answer lies in genes that control the growth of certain organs in the baby. The placenta is a particularly important organ for how well the baby grows given that it provides the maternal nutrients and oxygen that the baby needs. We believe that proteins that sit at the membrane of placental cells and specialize in transport of nutrients across the placenta are important in supplying nutrients for growth. We predict that a decrease in number or activity of these proteins will mean that the baby will be less nourished and not able to grow properly. We plan to test our hypothesis by using mouse models where pups are born small due to the removal of amino-acid System A transporters. We plan to accurately measure how well the nutrients are transferred across the placenta in these animals, how well organs such as liver, brain and placenta cope with this and what diseases these mice develop soon after birth and in later life. These experiments will provide important information about how fetal restriction comes about and of the role of amino-acid transporters in development and disease. Because transporter proteins are often used as drug targets or delivery systems our work could also have diagnostic and therapeutical applications.