Sphingosine-1-phosphate and vitamin D as modifiable essential mediators of human placental development

在怀孕期间，胎盘形成了母亲和婴儿之间的物理联系。它的工作之一是将母体血液中的营养物质和氧气输送到胎儿血液中。血液流动通常是通过挤压或放松血管的弹性壁来控制的，这样它们就会根据需要变窄或变宽。然而，在怀孕期间，子宫内母体血管的壁被称为滋养细胞的胎盘细胞侵入、破坏和重建，使血管不断变宽。这确保胎盘有足够的血液供应，为发育中的婴儿提供正常生长所需的所有构件。先前发表的研究证据表明，母体子宫的正常侵入不足导致妊娠疾病，如先兆子痫和胎儿生长受限。如果血管没有得到适当的改变，母亲可能会患重病，婴儿可能出生得太小或太早。这还会对婴儿的健康产生终身影响，因为这样的怀孕会增加婴儿成年后患肥胖症、心血管疾病或糖尿病的几率。目前，还没有办法纠正胎盘发育中的这些缺陷。制药公司不愿生产用于怀孕的药物，因为他们担心新产品会伤害未出生的婴儿，并希望避免昂贵的诉讼。相反，他们投资于其他研究领域，使医生在治疗孕妇方面几乎没有选择。这个问题的一个潜在解决方案是利用人体自然合成的化合物，如激素，或利用针对相关途径但已开发用于其他疾病的药物。在这个提议中，我们计划研究滋养细胞的侵袭和转化是如何受到一种被称为鞘氨醇-1-磷酸（S1P）的脂质的影响的。已知S1P在其他器官系统和动物模型中控制细胞的运动，但对其在妊娠早期的作用知之甚少。到目前为止，我们使用母胎界面细胞模型的实验表明，对这种脂质作出反应所需的化学机制是存在的，S1P阻止滋养细胞移动。我们也有初步研究的数据表明，有可能改变化学机制，从而防止S1P的负面影响，这些初步发现很有趣，因为其他研究者最近的工作表明，患有先兆子痫和/或胎儿生长受限的妇女通常维生素d水平较低。在这里，我们希望使用人类和动物组织来创建更好的模型，以研究S1P对血管滋养细胞转化的影响。然后，我们将测试当S1P的活性被维生素D和其他潜在的S1P机制调节剂改变时，子宫内血管的破裂会发生什么；这些化合物已被开发用于治疗癌症和神经系统疾病。如果我们的结果是好的，我们将申请进一步的资金用于临床试验，在伴有先兆子痫或胎儿生长受限的妊娠妇女中测试这些药物。迫切需要新的方法来解决由妊娠疾病引起的次优胎儿生长；胎儿生长异常不仅对个别家庭造成毁灭性后果，而且还造成与产科/新生儿护理和成人慢性病管理相关的重大社会和经济负担。

During pregnancy, the placenta forms the physical connection between a mother and her baby. One of its jobs is to transfer nutrients and oxygen from maternal to fetal blood. Blood flow is normally controlled by squeezing or relaxing the elastic walls of blood vessels, so that they become narrower or wider as required. In pregnancy however, the walls of the maternal vessels in the womb are invaded, broken down and rebuilt by placental cells, called trophoblast, to make the vessels constantly wide. This ensures that the placenta is supplied with sufficient blood to provide the developing baby with all the building blocks it needs to grow properly. Evidence from previously published work suggests that the normal invasion of the mother's womb is deficient in pregnancy diseases such as pre-eclampsia and fetal growth restriction. If the blood vessels aren't altered properly, the mother can become seriously ill and the baby can be born too small or too early. There's also a life-long impact on health as infants from such pregnancies have an increased chance of developing obesity, cardiovascular disease or diabetes in adulthood.Currently, there is no way to correct these defects in placental development. Drug companies shy away from making drugs for use in pregnancy because they are fearful of harming unborn babies with their new products, and want to avoid expensive lawsuits. Instead, they invest in other areas of research, leaving doctors with few alternatives for treating pregnant women. One potential solution to this problem is to exploit compounds, such as hormones, that are naturally synthesized by the body, or to utilize drugs that target relevant pathways but have been developed for other diseases. In this proposal we plan to investigate how trophoblast invasion and transformation of maternal blood vessels are affected by a lipid known as sphingosine-1-phosphate (S1P). S1P is known to control the movement of cells in other organ systems and animal models, but little is known about its role during early pregnancy. So far, our experiments, using models of the cells at the maternal-fetal interface, suggest that the chemical machinery needed to respond to this lipid is present and that S1P stops the trophoblast from moving. We also have data from pilot studies to suggest that it might be possible to alter the chemical machinery, and therefore prevent the negative effects of S1P, using vitamin D. These preliminary findings are interesting because recent work by other investigators has revealed that the women with pre-eclampsia and / or fetal growth restriction often have low levels of vitamin D.Here we want to use human and animal tissue to create better models for studying the effect of S1P on trophoblast transformation of blood vessels. We will then test what happens to the breakdown of the vessels from the womb when the activity of S1P is altered by vitamin D and other potential regulators of the S1P machinery; such compounds have been developed as therapies for cancer and neurological disease. If our results are good, we would apply for further funding for a clinical trial to test the drugs in women whose pregnancies are complicated by pre-eclampsia or fetal growth restriction.Novel approaches to tackling the sub-optimal fetal growth caused by pregnancy disease are desperately needed; not only do fetal growth abnormalities have devastating consequences for individual families, they contribute to the significant societal and economic burden associated with obstetric/neonatal care and the management of adult chronic disease.