Relaxin signalling in the endometrium and the regulation of early pregnancy

松弛素是一种荷尔蒙，在卵巢和子宫中产生，对支持子宫的生长发育，使年轻胚胎能够正确着床起着非常重要的作用。事实上，早孕丢失与血液中松弛素水平的变化有关。人们对松弛素在子宫中的作用知之甚少。该项目旨在解决这一重要功能，并利用培养的子宫细胞，这些细胞取自因子宫肌瘤或类似疾病接受子宫切除术的妇女的组织。当这些细胞在培养中生长时，我们可以在体外模拟怀孕早期发生的许多事件，导致细胞分化和生长，就像它们在体内一样。松弛素似乎通过使所谓的基质细胞中第二信使cAMP的浓度持续大幅增加而对这些细胞发挥重要作用。正是这个阵营导致了许多对健康怀孕至关重要的变化。了解这些影响背后的分子机制将有助于我们首先了解子宫是如何接受植入胚胎的，并可能解释为什么一些妇女在怀孕早期失去婴儿，或出现与胎盘发育相关的一些负面症状，如生长受限和先兆子痫。松弛素似乎通过一种名为LGR7的新型细胞表面受体来刺激细胞。虽然这种受体在结构上看起来像许多其他激素的受体，属于所谓的G蛋白偶联受体，但它的行为与自然子宫细胞中的不同。相反，它似乎利用了细胞内全新的信号通路。该项目旨在揭示和理解这些新的途径，从而不仅为早期妊娠问题的诊断和治疗提供重要的信息，而且对所有其他类似的受体也具有相关性。

Relaxin is a hormone, that is made in the ovary and the uterus, and plays a very important role in supporting the growth and development of the uterus so that the young embryo can implant properly. In fact, early pregnancy loss is associated with altered levels of relaxin in the blood. Very little is known about how relaxin works in the uterus. This project aims to address this important function, and makes use of cultured uterine cells prepared from tissues taken from women undergoing hysterectomy for fibroids or similar illnesses. When these cells are grown in culture, we can mimic in vitro many of the events that occur in early pregnancy, causing the cells to differentiate and grow just as they would in vivo. Relaxin appears to exert its important effects on these cells by causing the concentration of the second messenger cAMP in the so-called stromal cells to increase greatly and in a sustained manner. It is this cAMP which is then responsible for many of the changes which are essential for healthy pregnancy. A knowledge of the molecular mechanisms behind these effects would help us firstly to understand how the uterus becomes receptive to an implanting embryo, and may explain why some women lose their babies in early pregnancy, or develop some of the negative symptoms associated with placental development such as growth restriction and preeclampsia. Relaxin appears to stimulate cells through the mediation of a new type of cell surface receptor, called LGR7. Whilst structurally this receptor looks like those for many other hormones, belonging to the group of so-called G-protein coupled receptors, it does not behave like these in natural uterine cells. Instead it appears to make use of completely new signaling pathways inside the cells. This project aims to unravel and understand these new pathways, thus providing information not only of importance for diagnosis and treatment of early pregnancy problems, but also of relevance for all other similar receptors.