Dissecting IGF regulation of cell turnover in an integrated cellular system: the human placenta as a model

在怀孕期间，胎儿的生长依赖于母亲血液中的食物和氧气的转移，以及胎儿废物的反向转移。这些交换过程是由胎盘进行的。因此，胎盘在怀孕早期发育是胎儿正常发育的先决条件，事实上，在怀孕4个月之前，胎盘比胎儿大。如果胎盘发育不正常，那么胎儿的营养和氧气供应就会受到影响，导致发育受损。所有婴儿中有3%-10%将遭受胎儿发育障碍。这些婴儿中的许多人死亡，或者，如果他们真的活了下来，他们更有可能在童年时期生病或残疾。此外，出生时身材矮小会对健康产生终生影响，因为这些人成年后患心脏病或糖尿病的风险要大得多。对老鼠遗传学的研究表明，胰岛素样生长因子(IGFS)家族的激素是帮助胎盘生长所必需的。我们现在需要知道这是否也适用于女性；如果是这样的话，给母亲注射IGF可能会促进胎盘和胎儿的生长。直接问这个问题存在明显的伦理障碍，但我们已经开发出了新的方法，通过这种方法，胎盘碎片可以在试管中保持几天的生命，这段时间足够长，足以控制和测量生长。我们已经获得的结果表明，IGF确实能促进人类胎盘细胞的生长。在这个项目中，我们将使用在受控实验室环境中维护的胎盘组织来研究从母体一侧释放的IGF如何刺激生长。首先，我们将找出IGF是如何进入胎盘的。胎盘表面(称为合胞体)起到了屏障的作用，阻止细菌和其他有害物质到达胎儿。IGF以尚不为人所知的方式跨越了这一障碍。我们将通过观察IGF如何穿过合胞体来确定它是如何进入胎盘的。我们将确定被称为磷酸酶(PTP)的蛋白质是否与IGFS协同作用。众所周知，PTP有助于其他细胞和器官的生长。为了做到这一点，我们需要开发一些新的方法来消除活的胎盘组织中的磷酸酶，然后我们将看看IGFS是否仍然能让胎盘中的细胞生长。除了了解IGFS的工作原理(这可能最终导致治疗婴儿发育不正常的怀孕)外，该项目中提出的技术发展令人兴奋，因为胎盘是一个易于接触的复杂多细胞系统，它为人类细胞信号提供了比常用细胞系、动物或低等生物更好的模型。我们的结果将使我们深入了解生长信号在组织和有机体中是如何协调的，我们打算它们应该导致胎盘作为广泛适用的药物筛选目标系统的发展。

During pregnancy, growth of the fetus depends on the transfer of food and oxygen from the mother's blood, and transfer of fetal waste products in the opposite direction. These exchange processes are carried out by the placenta. Development of a placenta very early in pregnancy is therefore a prerequisite for normal fetal growth, and indeed the placenta is larger than the fetus until about 4 months of pregnancy. If the placenta doesn't develop properly then the nutrient and oxygen supply to the fetus is compromised, resulting in impaired growth. 3-10% of all babies will have suffered impaired fetal growth. Many of these babies die or, if they do survive, they are more likely to be ill or disabled during childhood. In addition, being small at birth has a life-long impact on health as the risk of developing heart disease or diabetes in adulthood is much greater in these individuals. Studies of mouse genetics have shown that a family of hormones known as insulin-like growth factors (IGFs) are required to help the placenta grow. We now need to know whether this is also true in women; if so, placental and fetal growth might be enhanced by administering IGF to the mother. There are obvious ethical barriers to asking this question directly, but we have developed new methods by which pieces of placenta can be kept alive for several days in the test tube, a time sufficiently long to be able to manipulate and measure growth. We have already obtained results that show IGF indeed makes human placental cells grow. In this project we will use placental tissue maintained in a controlled laboratory environment to investigate how IGF delivered from the maternal side stimulates growth. First we will find out how IGF gets into the placenta. The placental surface (called the syncytium) acts as a barrier that prevents bacteria and other harmful agents from reaching the fetus. IGF surmounts this barrier in ways that are not yet understood. We will establish how IGF can get into the placenta, by looking at how it can cross the syncytium. We will determine if proteins called phosphatases (PTPs), which are known to help other cells and organs grow, act in concert with IGFs. In order to do this, we will need to develop some new methods for eliminating ('knock down') phosphatases from living placental tissue, and then we will see if IGFs can still make cells in the placenta grow. In addition to finding out how IGFs work, which may eventually lead to treatments for pregnancies in which the baby doesn't grow properly, the technological developments proposed in this project are exciting because the placenta is a readily accessible, complex multicellular system that provides a better model for human cellular signalling than commonly used cell lines, animals or lower organisms. Our results will give insight into how growth signals are coordinated in tissues and organisms, and we intend they should lead on to the development of the placenta as a widely applicable target system for drug screening.