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个婴儿出生的三个婴儿很小。小婴儿比正常大小的婴儿具有较少的储备和承受劳动压力的能力。在生命的最初几天，他们的死亡和疾病风险更高，在以后的生活中患疾病，包括糖尿病，高血压和心脏病。因此，胎儿生长限制是一个主要的健康问题。为什么婴儿在子宫中未能发挥其增长潜力，而在大多数情况下，实际上它的发生方式尚不清楚。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中某些器官的生长的基因。胎盘是婴儿在提供婴儿所需的母体营养和氧气的情况下的生长效果特别重要的器官。我们认为，位于胎盘细胞膜的蛋白质并专门从事整个胎盘的养分运输对于供应营养的生长很重要。我们预测，这些蛋白质的数量或活性减少将意味着婴儿的营养较低，无法正常生长。我们计划通过使用小鼠模型来测试我们的假设，因为幼崽出生的小鼠模型由于去除氨基酸系统A转运蛋白而较小。我们计划准确地测量这些动物中的养分在整个胎盘上的转移程度，肝脏，脑和胎盘等器官如何应对这种动物，以及这些小鼠出生后不久和以后生命的疾病的发展。这些实验将提供有关胎儿限制如何产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。由于转运蛋白通常被用作药物靶标或输送系统，因此我们的工作也可能具有诊断和治疗应用。

项目成果

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

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