Multiscale analysis of extracellular regulation of BMP signalling

骨形态发生蛋白（BMPs）是一种强大的“生长因子”，对几乎所有器官和组织的发育以及随后维持正常的组织结构和功能至关重要。在发育过程中，细胞感知来自环境的信号，并将其转化为细胞反应，从而改变它们的行为，并经常改变它们将成为的细胞类型。这里提出的研究集中于一种主要的信号类型，BMP信号，它在早期胚胎中至关重要，在那里它控制着细胞沿前向后轴的命运。BMP的作用由抑制或增强BMP信号的调节蛋白控制，尽管它们如何做到这一点尚不清楚。抑制剂是与bmp结合的大型蛋白质，从而阻止它们与受体相互作用并向细胞发送信息。我们感兴趣的是两种BMP调节因子，Chordin和Tsg，这是正确胚胎发育所必需的。然而，目前这些蛋白复合物及其相互作用的细节很少，这是理解BMP调控的主要障碍。因此，我们研究的主要目的是了解这些调节因子调节BMP信号的机制。我们将通过使用显微镜可视化Chordin和Tsg的位置并分析它们的结构来确定这些调节蛋白如何相互作用和bmp来实现这一目标。Chordin和Tsg在从果蝇到人类的简单生物胚胎发育过程中控制BMP信号。因此，我们将使用果蝇作为本研究的模型，因为果蝇作为研究生物具有许多优点，包括生命周期快，易于维护，易于遗传和基因组编辑。考虑到Chordin和Tsg在果蝇和人类中都能调节BMP信号，我们的发现将与人类生物学直接相关。我们的研究结果将使我们更好地理解BMP调控是如何发生的，以及这些相互作用是如何支撑Chordin和Tsg在组织组装和胚胎发育中发挥重要作用的。这项研究的结果不仅对理解胚胎发育很重要，而且最终将允许设计调节BMP的新疗法，因为当细胞接收到过多或不足的BMP信号时，许多人类疾病就会出现。此外，干细胞领域的一个主要目标是能够有效地将干细胞分化成特定的细胞类型。这个过程通常是通过添加或抑制bmp来实现的。因此，通过增加对如何精确操纵BMP活性的理解，我们的结果也将对干细胞领域产生重大影响。

The Bone Morphogenetic Proteins (BMPs) are powerful "growth factors" which are essential for development of nearly all organs and tissues, as well as subsequently maintaining normal tissue structure and function. During development, cells sense signals from their environment that are converted into cellular responses, resulting in a change in their behaviour and often the type of cell they will become. The research proposed here focuses on one major type of signal, the BMP signal, which is critically important in early embryos, where it controls cell fates along the front to back axis.The action of BMPs is controlled by regulator proteins that can inhibit or enhance the BMP signal, although how they do this is not yet understood. The inhibitors are large proteins that bind to the BMPs, thereby preventing them from interacting with their receptors and sending a message to the cell. We are interested in two BMP regulators, Chordin and Tsg, which are necessary for correct embryonic development. However, there are currently few details of these protein complexes and their interactions which presents a major obstacle to understanding BMP regulation. The main aim of our research therefore is to understand the mechanisms by which these regulators modulate BMP signals. We will achieve this by visualising the location of Chordin and Tsg using microscopy and analysing their structures to determine how these regulator proteins interact with each other and BMPs.Chordin and Tsg control BMP signalling during development of embryos from simple organisms, such as fruitflies, up to humans. Therefore, we will use the fruitfly Drosophila as a model for this research as it has many advantages as a research organism, including a rapid life cycle, ease of maintenance and amenability to genetics and genome editing. Given that Chordin and Tsg regulate BMP signalling in both fruitflies and humans, our findings will be directly relevant to human biology. Our results will allow us to gain a better understanding of how BMP regulation occurs and how these interactions underpin the important roles that Chordin and Tsg play in tissue assembly and embryo development. Results from this study will not only be important for understanding embryonic development, but will ultimately allow the design of new therapeutics modulating BMPs, as many human diseases arise when cells receive excessive or insufficient BMP signal. Moreover, a major goal in the stem cell field is to be able to efficiently differentiate stem cells into a particular cell type. Often this process is achieved by adding or inhibiting BMPs. Therefore, by increasing understanding of precisely how to manipulate BMP activity, our results will also be of major benefit to the stem cell field.