A SPATIO-TEMPORAL MAP OF THE DEVELOPMENTAL FLY INTERACTOME

发育，即细胞分化和分裂以创造新生命的过程，是一个迷人的过程，受我们基因之间复杂的相互作用的支配。随着时间的推移，通过改变这些基因的水平和特定性质，仔细控制这些基因，更具体地说，控制它们的蛋白质产物，决定了细胞的命运和它们将形成的组织。除了时机，基因在细胞内表达的位置及其蛋白产物的活性也是决定功能的重要因素。原则上，解决这一难题所需的信息包含在基因组序列中。然而，我们目前缺乏发育过程中发生的一切的全貌，原因有几个：我们不知道每个基因在每个时间点有多少表达，我们不知道每个基因的哪个版本(异构体)表达，我们不知道每个基因与其他哪些配对基因相互作用，也不知道这种情况发生在细胞中的什么地方。尽管其中一些信息是已知的，但正确理解发育信号所需的大部分相关知识仍然缺失。关键的是，也许对这项提议来说最重要的是，我们缺乏全面的数据，特别是在*蛋白质*水平上(功能真正决定的)。在这项提议中，我们的目标是利用实验和计算后基因组科学来缩小这一差距，以研究模式生物(果蝇)中的特定信号通路。重要的是，我们已经有了必要的方法来完成这项工作，将英国蛋白质组学(包括实验和计算)专家与苍蝇基因组学和信号专家聚集在一起，以应对这一挑战。这包括由在基因组序列注释和预测蛋白质功能方面处于领先地位的团体提供的最先进的生物信息学工具。重要的是，他们现在能够考虑上面讨论的“未知数”，例如不同的异构体及其对相互作用的伙伴蛋白的可能影响。我们将根据重要信号蛋白的水平、异构体、相互作用和位置来描述发育中的苍蝇蛋白质组，以便生成发育时空图。这将是发育生物学和基因组科学的重大进步，我们希望这将成为所有对基因功能和发育感兴趣的生物学家的重要资源，以及推进和整合研究它所需的技术。

Development, the process by which cells differentiate and divide to create new life is a fascinating process that is governed by the complex interplay between our genes. Careful control of these genes, and more specifically their protein products, by altering their levels and specific nature over time dictates the fate of cells and what tissues they will form. As well as the timing, the location within the cell where a gene is expressed and its protein product is active is also important in determining function. The information needed to solve this puzzle is, in principle, contained within the genome sequence. However, we currently lack the full picture of what happens during the course of development for several reasons: we don't know how much of each gene is expressed at each time point, we don't know which version (isoform) of each gene is expressed, and we don't know which other partner genes each gene interacts with nor where in the cell this happens. Although some of this information is known, much of the relevant knowledge needed to properly understand developmental signalling is missing. Crucially, and perhaps mostly importantly for this proposal, we lack comprehensive data specifically at the *protein* level (where function is really determined). In this proposal we aim to close the gap, using both experimental and computational post-genome science, to study specific signalling pathways in a model organism (the fruit fly). Importantly, we already have the necessary methods in place to do this, bringing together UK experts in proteomics (both experimental and computational) with fly genomics and signalling experts to tackle this challenge. This includes state-of-the-art bioinformatics tools from groups who lead the way in the annotation of genome sequences and predicting protein function. Importantly, they are now able to consider the "unknowns" discussed above, such as different isoforms and their likely effects on interacting partner proteins. We will characterise the developmental fly proteome, in terms of the levels, isoforms, interactions and locations of the important signalling proteins in order to generate a developmental spatio-temporal map. This will be a major advance in both developmental biology and genome science, which we hope will form an important resource for all biologists interested in gene function and development, as well as advancing and integrating the technologies needed to study it.