Regulation of melatonin receptor expression by gonadotrophin-releasing hormone (GnRH)

褪黑激素在生物学上有许多重要的功能，其中许多涉及到对其他激素系统的调节。我们对褪黑素生物学的大部分了解来自对成年动物的研究，在这些研究中，褪黑素只作用于全身有限数量的组织。然而，已知胎儿和新生儿体内更多的组织对褪黑素敏感，而不是成年人。到目前为止，在发育过程中对褪黑素更广泛的敏感性的生物学意义尚不清楚。我们可以开始探索褪黑激素这些未确定的角色的一种方法是对这些发育变化背后的过程的本质有一个清楚的了解。这个项目将建立在申请人最近的研究基础上，并帮助我们了解组织在发育过程中如何改变其对褪黑素的敏感性。申请人最近发表了多篇研究论文，调查了脑下垂体促性腺激素细胞对褪黑素敏感性的发育调节，这是研究褪黑素发育生物学的最具特色的模型。垂体促性腺激素细胞对生殖功能是必不可少的，包括青春期发育。我们提供的初步证据表明，脑源性化学物质促性腺激素释放激素(GnRH)的发育分泌是降低促性腺激素细胞对褪黑激素敏感性的主要刺激因素。此外，GnRH的作用似乎是由一种名为Egr-1的细胞信号分子介导的。目前的项目将首次对促性腺激素释放激素在确定褪黑素敏感性中的作用进行详细的调查。我们将使用一系列互补的实验技术来操作GnRH和Egr-1的活性，然后评估这些操作对褪黑素敏感性的影响。这些技术将包括使用在实验室条件下培养的分离细胞，以最大限度地减少使用动物。这项工作的结果将对科学家和公众产生重要影响。项目完成后，我们将对褪黑素的生物学作用有更深入的了解，更广泛地说，我们将深入了解激素分泌细胞的发育变化。由于褪黑素在一些国家可以作为一种非处方药作为食物补充，这项工作也将有助于我们了解在某些情况下，例如在怀孕期间服用褪黑素可能带来的健康风险。

The hormone melatonin has many important functions in biology, many of which involve the regulation of other hormonal systems. Most of our understanding of melatonin biology comes from studies of adult animals, in which melatonin only acts on a restricted number of tissues throughout the body. However, it is known that more tissues in the body are sensitive to melatonin in foetuses and newborns than in adults. To date, the biological significance of the broader sensitivity to melatonin during development is not known. One way in which we can start to explore these undefined roles of melatonin is to gain a clear understanding of the nature of the processes that underlie these developmental changes. This project will build upon recent studies by the applicant and help us to understand how tissues change their sensitivity to melatonin during development. The applicant has recently published multiple research papers investigating the developmental regulation of melatonin sensitivity in gonadotroph cells of the pituitary gland, which is the best-characterised model for studying the developmental biology of melatonin. Pituitary gonadotroph cells are essential for reproduction function, including pubertal development. We have provided preliminary evidence to suggest that the developmental secretion of a brain-derived chemical, gonadotrophin-releasing hormone (GnRH), is the primary stimulus for decreasing sensitivity to melatonin in gonadotroph cells. Furthermore, the effects of GnRH appear to be mediated by a cellular signalling molecule called Egr-1. The current project will be the first to provide a detailed investigation into the role of GnRH in determining melatonin sensitivity. We will use a range of complementary experimental techniques to manipulate both GnRH and Egr-1 activity and then evaluate the effects of these manipulations on melatonin sensitivity. These techniques will include the use of isolated cells grown in laboratory conditions, in order to minimise the use of animals. The results of this work will have important implications for scientists and the public. On completion of the project, we will have a greater understanding of the biological role of melatonin and, more generally, an insight into developmental changes in hormone-secreting cells. As melatonin is available over-the-counter as a food supplement in some countries, this work will also help us to understand potential health risks of taking melatonin in certain situations e.g. during pregnancy.