Amino acid transport through the placenta: an experimental and modelling investigation

通过胎盘的氨基酸转运：实验和建模研究

• 批准号: BB/I011315/1
• 负责人: Rohan Lewis
• 金额: $ 43.78万
• 依托单位: University of Southampton
• 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%2FI011315%2F1
• 关键词: Amino; acid; transport; through; placenta

While in the womb the baby obtains all the nutrients it requires for growth and development from the placenta. This organ transfers nutrients from maternal blood to the baby's blood. If the placenta does not transfer enough nutrients, the fetus will not be able to grow adequately and may be born too small. Babies who are born too small are more likely to develop health problems, both in early life and in adulthood. To understand the normal processes by which babies grow in the womb and to understand why this process is sometimes disturbed, we need to fully appreciate how nutrients are transported across the placenta. Understanding normal placental function will allow us to define what might go wrong when growth of the baby becomes impaired and how this might be prevented or treated at an early stage. In this project we will develop a computer model of how the placenta functions which can be used to better understand how the placenta works normally and also how it can go wrong in a difficult pregnancy. We are particularly interested in the placental transfer of amino acids. These are the building blocks of proteins which form muscles and the cellular 'machinery' essential for life. Thus, amino acids are an important class of nutrients, and their placental transfer is essential for optimal growth of the baby in the womb. In pregnancies where the baby was born small, placental amino acid transport has been shown to be lower than in babies of normal birth weight. Placental amino acid transfer is a complex process which is dependent on (i) amino acid transporters - (carriers) which take nutrients from maternal blood and release them into fetal blood, (ii) on blood flow through the placenta, (iii) on the internal structure of the placenta, and (iv) on the levels of amino acids in maternal and fetal blood as well as inside the cells which make up the placenta. The way these factors affect amino acid transfer cannot be understood in isolation as there are complicated interdependent interactions between them. Therefore, developing a computer model of these complex interactions will allow us to study how the placenta works as an integrated system. We have already designed a simple model that simulates the function of amino acid transporters in the human placenta and which can predict the transport of up to 3 amino acids at any one time. We have tested this model by comparing it to what we observe experimentally in placentas collected immediately after birth. These tests show that the model can convincingly reproduce experimental data, but we now need to expand our system to accurately simulate the simultaneous transport of the entire set of 20 amino acids. Such a model must incorporate other influences on placental transport such as the internal structure and blood flow patterns of the placenta. Ultimately, a well validated virtual placental amino acid transport model will help to explain how the components of the normal placenta function to transport amino acids to the baby and sustain optimal growth. It will identify the most important factors which affect placental amino acid transport and will allow future studies to be focused on such factors that are likely to have the greatest impact, leading to the development of effective strategies to ensure babies grow optimally in the womb. These strategies may include algorithms to predict how mothers metabolic state may affect placental amino acid transport (e.g. in maternal diabetes, teenage pregnancy) and to develop personalised interventions or using the model to identify key targets for pharmacological interventions. Ultimately we intend that this work will contribute to the development of a fully-fledged Virtual Placenta, one that does not just model amino acid transport but all the placental functions.

在子宫内，婴儿从胎盘获得生长和发育所需的所有营养。这个器官将母体血液中的营养物质转移到婴儿的血液中。如果胎盘不能转移足够的营养，胎儿将无法充分生长，可能会出生太小。出生时太小的婴儿更有可能在早期和成年后出现健康问题。为了了解婴儿在子宫内生长的正常过程，以及为什么这个过程有时会受到干扰，我们需要充分了解营养物质如何通过胎盘运输。了解正常的胎盘功能将使我们能够确定当婴儿生长受损时可能出现的问题，以及如何在早期预防或治疗。在这个项目中，我们将开发一个胎盘功能的计算机模型，它可以用来更好地了解胎盘如何正常工作，以及它如何在困难的怀孕中出错。我们特别感兴趣的是氨基酸的胎盘转移。这些是蛋白质的组成部分，蛋白质形成肌肉和生命所必需的细胞“机器”。因此，氨基酸是一类重要的营养素，它们的胎盘转移对于婴儿在子宫内的最佳生长至关重要。在婴儿出生时很小的妊娠中，胎盘氨基酸运输已被证明低于正常出生体重的婴儿。胎盘氨基酸转移是一个复杂的过程，取决于（i）氨基酸转运蛋白（载体），其从母体血液中摄取营养物质并将其释放到胎儿血液中，（ii）通过胎盘的血流，（iii）胎盘的内部结构，以及（iv）母体和胎儿血液以及构成胎盘的细胞内的氨基酸水平。这些因素影响氨基酸转移的方式不能孤立地理解，因为它们之间存在复杂的相互依赖的相互作用。因此，开发这些复杂相互作用的计算机模型将使我们能够研究胎盘作为一个集成系统如何工作。我们已经设计了一个简单的模型，它模拟了人体胎盘中氨基酸转运蛋白的功能，并且可以预测在任何一个时间最多3种氨基酸的转运。我们通过将其与我们在出生后立即收集的胎盘中观察到的实验结果进行比较来测试该模型。这些测试表明，该模型可以令人信服地重现实验数据，但我们现在需要扩展我们的系统，以准确地模拟整个20种氨基酸的同时运输。这样的模型必须包括对胎盘运输的其他影响，例如胎盘的内部结构和血流模式。最终，一个经过充分验证的虚拟胎盘氨基酸转运模型将有助于解释正常胎盘的组成部分如何向婴儿转运氨基酸并维持最佳生长。它将确定影响胎盘氨基酸转运的最重要因素，并将使未来的研究集中在可能产生最大影响的因素上，从而制定有效的策略，以确保婴儿在子宫内最佳地生长。这些策略可能包括预测母亲代谢状态如何影响胎盘氨基酸转运的算法（例如，在母亲糖尿病，少女怀孕中），并制定个性化干预措施或使用模型来确定药物干预的关键目标。最终，我们希望这项工作将有助于开发一个完全成熟的虚拟胎盘，它不仅模拟氨基酸转运，还模拟胎盘的所有功能。

项目成果

Estrone sulphate uptake by the microvillous membrane of placental syncytiotrophoblast is coupled to glutamate efflux.

• DOI: 10.1016/j.bbrc.2018.10.074
• 发表时间: 2018-11-17
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Lofthouse EM;Cleal JK;O'Kelly IM;Sengers BG;Lewis RM
• 通讯作者: Lewis RM

Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast.

谷氨酸循环可能驱动有机阴离子在人胎盘合成细胞基底膜上的转运。

• DOI: 10.1113/jp270743
• 发表时间: 2015-10-15
• 期刊: The Journal of physiology
• 作者: Lofthouse EM;Brooks S;Cleal JK;Hanson MA;Poore KR;O'Kelly IM;Lewis RM
• 通讯作者: Lewis RM

Integration of computational modeling with membrane transport studies reveals new insights into amino acid exchange transport mechanisms.

• DOI: 10.1096/fj.14-267773
• 发表时间: 2015-06
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Widdows KL;Panitchob N;Crocker IP;Please CP;Hanson MA;Sibley CP;Johnstone ED;Sengers BG;Lewis RM;Glazier JD
• 通讯作者: Glazier JD

Computational modelling of placental amino acid transfer as an integrated system.

• DOI: 10.1016/j.bbamem.2016.03.028
• 发表时间: 2016-07
• 期刊: Biochimica et biophysica acta
• 作者: Panitchob N;Widdows KL;Crocker IP;Johnstone ED;Please CP;Sibley CP;Glazier JD;Lewis RM;Sengers BG
• 通讯作者: Sengers BG

Phenylalanine transfer across the isolated perfused human placenta: an experimental and modeling investigation.

• DOI: 10.1152/ajpregu.00405.2015
• 发表时间: 2016-02-01
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Lofthouse EM;Perazzolo S;Brooks S;Crocker IP;Glazier JD;Johnstone ED;Panitchob N;Sibley CP;Widdows KL;Sengers BG;Lewis RM
• 通讯作者: Lewis RM