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

系统A氨基酸转运蛋白在胎儿生长发育中的生理作用

• 批准号: BB/I014594/1
• 负责人: Miguel Constancia
• 金额: $ 60.67万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI014594%2F1
• 关键词: Physiological; roles; System; amino; acid

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.

每 100 个婴儿中就有 3 个出生时体型较小。与正常体型的婴儿相比，小婴儿的储备能力和承受分娩压力的能力较差。他们在生命的最初几天内死亡和患病的风险较高，并且在以后的生活中患糖尿病、高血压和心脏病等疾病的风险也较高。因此，胎儿生长受限是一个主要的健康问题。大多数情况下，尚不清楚为什么婴儿在子宫内无法发挥其生长潜力，以及它是如何发生的。我们正在研究胎儿限制是如何发生的。我们认为答案在于控制婴儿某些器官生长的基因。胎盘是影响婴儿生长的特别重要的器官，因为它提供婴儿所需的母体营养和氧气。 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.我们预测，这些蛋白质数量或活性的减少将意味着婴儿的营养会减少，并且无法正常生长。我们计划使用小鼠模型来检验我们的假设，在这些小鼠模型中，由于氨基酸系统 A 转运蛋白的去除，幼崽出生时体型较小。我们计划准确测量营养物质在这些动物体内通过胎盘转移的情况，肝脏、大脑和胎盘等器官应对这种情况的情况，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。这些实验将提供有关胎儿限制如何发生以及氨基酸转运蛋白在发育和疾病中的作用的重要信息。由于转运蛋白通常用作药物靶点或递送系统，因此我们的工作也可以具有诊断和治疗应用。

项目成果

Genome-wide oxidative bisulfite sequencing identifies sex-specific methylation differences in the human placenta.

• DOI: 10.1080/15592294.2018.1429857
• 发表时间: 2018
• 期刊: Epigenetics
• 影响因子: 3.7
• 作者: Gong S;Johnson MD;Dopierala J;Gaccioli F;Sovio U;Constância M;Smith GC;Charnock-Jones DS
• 通讯作者: Charnock-Jones DS

Deletion of the Imprinted Phlda2 Gene Increases Placental Passive Permeability in the Mouse.

• DOI: 10.3390/genes12050639
• 发表时间: 2021-04-25
• 期刊: Genes
• 影响因子: 3.5
• 作者: Angiolini E;Sandovici I;Coan PM;Burton GJ;Sibley CP;Fowden AL;Constância M
• 通讯作者: Constância M