Regulation of the Rho GEF Pebble in Fibroblast Growth Factor dependent cell migration

细胞移动的能力在人体内是一个高度受调控的过程。细胞可以发送和接收信号，使它们能够以受控的方式改变生物体中的位置。这些信号作用于细胞内一种名为细胞骨架的机器，该机器允许细胞在有机体或底物上向前推进。细胞迁移调控的缺陷是许多严重的人类疾病和大量先天疾病的原因。因此，研究这些信号的分子细节及其在细胞迁移中的作用对于我们理解人类疾病和开发针对这些疾病的治疗方法至关重要。由于明显的原因，我们不能在人类身上进行实验，因此对人类细胞疾病途径的研究经常受到阻碍。一种可能性是利用患病的细胞或组织，但这些细胞或组织不再与整个有机体接触，因此只能提供有限的洞察力。另一种可能性是使用所谓的模型生物。由于所有多细胞动物的主要遗传谱惊人地相似，我们可以使用简单的生物来研究人类疾病的途径。我们实验室正在使用果蝇黑腹果蝇，它在生物医学研究中已经使用了100多年。果蝇的力量在于它很容易通过突变和其他修饰来操纵它的基因。我们之前的研究已经确定了一条由成纤维细胞生长因子触发的信号通路，该通路负责果蝇胚胎细胞迁移的开始和方向性。由于非常相似的分子在人类胚胎中发挥着相似的功能，我们的研究成果可以移植到人类身上。为了确定通过成纤维细胞生长因子信号调节细胞迁移的分子，我们进行了大规模的遗传学实验。这些基因筛查发现了其他基因的突变，然后我们证明了这些基因对细胞迁移过程中细胞骨架的调节非常重要。在这个研究项目中，我们计划确定这种调节是如何在分子水平上发生的，以及生长因子如何改变细胞骨架的一个重要调节因子的活性和定位。我们预计，这项研究的结果将为药物发现项目的研究提供新的机会，以建立能够检测小分子化合物的分析方法，从而为细胞迁移异常的疾病提供新的治疗方法。

The capability of cells to move is a highly regulated process in the human body. Cells can send and received signals that enable them to change position in an organism in a controlled fashion. These signals act upon a machine within the cell called the cytoskeleton, which allows cells to propel themselves forward in an organism or upon a substrate. Defects in the regulation of cell migration are the cause of many severe human diseases and a plethora of congenital disorders. Therefore to investigate the molecular detail of the signals and their action in cell migration is of utmost importance for our understanding of human diseases and to develop treatments against them.Research on human cellular disease pathways is often hampered by the fact that we cannot do experiments with humans for obvious reasons. One possibility is to utilise diseased cells or tissues, but these are no longer in contact with the entire organism and thus only provided limited insight. Another possibility is the use of so called model organisms. As the principal genetic repertoire of all multicellular animals is surprisingly similar, we can use simple organisms to investigate human disease pathways. Our laboratory is using the fruit fly Drosophila melanogaster, which has been employed for over 100 year in biomedical research. The power of Drosophila lies in its ease to manipulate its genes by mutations and other modifications. Our previous research has identified a signalling pathway triggered by a Fibroblast Growth Factor that is responsible for the onset and the directionality of cell migration in the fly embryo. As very similar molecules exerts similar functions in human embryos, our research results are transferable to humans.To identify the molecules that are involved in the regulation of cell migration through Fibroblast Growth Factor signalling we have conducted large scale genetic experiments. These genetic screens found mutations in other genes, which we then showed to be important for the regulation of the cytoskeleton during cell migration. In this research project we plan to determine how this regulation occurs on the molecular level and how the growth factor can modify the activity and the localisation of an important regulator of the cytoskeleton. We expect that the results from this research will provide new opportunities for research in drug discovery projects to establish assays that can detect small compounds leading to novel treatments of diseases in which cell migration is abnormal.