Extracellular regulation of BMP signalling in development and disease

骨形态发生蛋白(BMP)通路是主要的细胞信号通路之一，对几乎所有人体器官和组织的发育都具有重要作用。与其在发育中的核心作用一致，BMP信号的错误调节会导致多种疾病，包括肾脏、血管和骨骼缺陷，以及许多癌症。因此，了解BMP途径的不同调控方式是至关重要的。这个项目的目的是用多学科的方法来了解BMP信号分子的细胞外调节，特别是一种名为短原肠形成(SOG)的BMP结合蛋白。将在果蝇和非洲爪哇的模式生物中研究BMP的调节，因为它们易于操作，对于果蝇，将采用各种遗传和基因组工程方法。首先，将使用一系列生物物理方法来研究SOG是如何与BMP结合并抑制BMP活性的。这一分析将使人们能够对SOG在体内的作用机制做出各种预测。这些预测将通过将特定的SOG突变形式引入果蝇和非洲爪哇胚胎并研究BMP信号和发育如何受到影响来直接检验。总体而言，该项目提供了一个在结构、分子、发育、遗传和基因组工程技术方面接受培训的独特机会。此外，从长远来看，更好地了解SOG在体内的功能将有助于开发新的医学策略来改善骨骼愈合，减少动脉粥样硬化。参考文献Winstanley，J.，Sawala，A.，Baldock，C.和Ahe，H.L.(2015)。在果蝇BMP梯度形成过程中，合成酶-底物连接消除了Tolloid-ECM相互作用。《eLife 4》，e05508.Troilo，H.，Zuk，A.V.，Tunney liffe，R.B.，Wohl，A.P.，Berry，R.，Collins，R.F.，Jowitt，T.A.，Sengle，G.和Baldock，C.(2014)。BMP拮抗剂Chordin的纳米级结构支持BMP的协同结合。S，A.111,13063.萨瓦拉，A.，萨克利夫，C.和阿什，H.L.(2012年).果蝇胚胎BMP胞外转运的多步分子机制。PNAS109,11222。书名/作者声明：[by][1][1][2][2]。二聚化和底物排斥在骨形态发生蛋白-1和哺乳动物类固醇调节中的作用。《学报》106,8561-6.王翔，Harris，R.E.，Bayston，L.J.和Ahe，H.L.(2008)。在果蝇中，IV型胶原蛋白调节BMP信号。大自然454，72-78。

The Bone Morphogenetic Protein (BMP) pathway, one of the major cell signalling pathways, is important for development of nearly all human organs and tissues. In line with its central role in development, misregulation of BMP signalling leads to a variety of diseases including kidney, vascular and skeletal defects, as well as numerous cancers. Therefore, it is critical to understand the different ways in which the BMP pathway is regulated. The aim of this project is to use a multidisciplinary approach to understand the extracellular regulation of BMP signalling molecules, with particular focus on a BMP binding protein called Short Gastrulation (Sog). BMP regulation will be investigated in the Drosophila and Xenopus model organisms as they are tractable to manipulation and in the case of Drosophila a variety of genetic and genome engineering approaches. Firstly, a range of biophysical approaches will be used to investigate how Sog binds to BMPs and inhibits BMP activity. This analysis will allow various predictions to be made about the mechanisms of action of Sog in vivo. These predictions will be directly tested by introducing specific mutant forms of Sog into the Drosophila and Xenopus embryos and investigating how BMP signalling and development are affected. Overall, this project offers a unique opportunity to be trained in structural, molecular, developmental, genetic and genome engineering techniques. Moreover, a better understanding of how Sog functions in vivo will in the longer term be useful for the development of novel medical strategies to improve bone healing, and reduce atherosclerosis.ReferencesWinstanley, J., Sawala, A., Baldock, C. and Ashe, H.L. (2015). Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation. eLife 4, e05508.Troilo, H., Zuk, A.V., Tunnicliffe, R.B., Wohl, A.P., Berry, R., Collins, R.F., Jowitt, T.A., Sengle, G. and Baldock, C. (2014). Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding. Proc Natl Acad Sci U S A. 111, 13063.Sawala, A., Sutcliffe, C. and Ashe, H.L. (2012). A multi-step molecular mechanism for BMP extracellular transport in the Drosophila embryo. PNAS 109, 11222. Berry R., Jowitt T.A., Ferrand J., Roessle M., Grossmann J.G., Canty-Laird E.G., Kammerer R.A., Kadler K.E. and Baldock C. (2009). Role of dimerization and substrate exclusion in the regulation of bone morphogenetic protein-1 and mammalian tolloid. Proc Natl Acad Sci 106, 8561-6.Wang, X., Harris, R.E., Bayston, L.J. and Ashe, H.L. (2008). Type IV collagens regulate BMP signalling in Drosophila. Nature 454, 72-78.