Egg to Embryo: Gene Regulatory Circuitry in Development

描述(由申请人提供)：这是一份申请续签现已14‘^年的计划项目。在这里，我们建议在解决和验证用于开发的基因调控网络(GRN)方面取得的巨大成功的基础上，建立新的方向。GRN在基因组调控代码方面为发育过程提供了因果解释，其中所有物种特定的发育过程最终都被编程。发展的GRN是一个概念性的、系统级的逻辑地图，我们已经证明它具有直接的预测能力。因此，GRNS在具有调控意义的功能基因组DNA序列和胚胎发生和身体计划形成的生物学之间架起了桥梁。他们通过指定调控相互作用来做到这一点，这些调控相互作用在不同的细胞领域中因果地推动了监管状态的进展。近几年来，该计划 负责任何发育中的动物有机体目前可用的最先进的发育GRN的实验解决方案。这是海胆胚胎内胚层区域规范所依据的GRN。最近，这项工作证明了当GRN接近完成时，它确实提供了对所有观察到的生物功能的解释。我们现在打算利用我们开发的越来越多的成功的技术和概念方法来进行GRN分析，以应对在此之前无法获得或甚至无法定义的挑战。目前或即将完成的海胆胚胎GRN包括胚胎的所有主要区域，从最早的合子基因组活动(卵裂开始)到原肠形成之前。此外，在当前时期的方案项目中，一个先进的 利用该计划项目首创的智力和技术方法，成功地构建了鸡的脑神经脊部的GRN。海胆胚胎GRN的Davidson组件(项目I)现在将扩展GRN分析，将整个胚胎包括在一个GRN模型中，这样更新每个部分的每一次输入，医疗实践将超越优雅形式的创可贴和单分子药物靶标的唯一途径将是在生命系统实际运行的组织水平上进行干预，特别是控制系统。这个项目涉及目前我们所拥有的基因组控制系统生物学的最先进的例子。它的成功结论将显示这些系统的结构是什么；如何考虑对它们进行干预；并直接为考虑发育活跃的调节基因突变在我们所知的多种形式的人类发育遗传病中的作用提供参考。医学研究界清楚地意识到这些点，并且该申请的PI经常被它的前瞻性成员要求进行合作、咨询、研讨会陈述等。

DESCRIPTION (provided by applicant): This is an application for renewal of a Program Project now in its 14'^ year. Here we propose to build in novel directions on the large success we have had in solving and authenticating gene regulatory networks (GRN) for development. GRNs provide causal explanations for developmental processes in the terms of the genomic regulatory code, in which all species-specific developmental processes are ultimately programmed. A developmental GRN serves as a conceptual, system-level logic map, which we have shown to possess direct predictive power. Thus GRNs bridge between functional genomic DNA sequence of regulatory significance and the biology of embryogenesis and body plan formation. They do this by specifying the regulatory interactions which causally drive the progression of regulatory states in diverse cellular territories. During recent years, this Program has been responsible for the experimental solution of the most advanced developmental GRN yet available for any developing animal organism. This is the GRN underlying the specification of the endomesodermal territories of the sea urchin embryo. Recently proof of the principle that as a GRN approaches completion it indeed provides explanation of all the observed biological, functions has been obtained in this work. We now intend to capitalize on the growing suite of successful technological and conceptual approaches to GRN analysis that we have developed, to confront challenges that heretofore were inaccessible, or could not even have been defined. Current or soon to be completed sea urchin embryo GRNs include all but one of the major domains of the embryo, from the earliest zygotic genomic activity (at the beginning of cleavage) to just before gastrulation. In addition, in the current period of the Program Project, an advanced GRN has been successfully constructed for the cranial neural crest of the chicken using the intellectual and technological approaches pioneered by this Program Project. The DAVIDSON COMPONENT (Project I) of the sea urchin embryo GRN will now expand GRN analysis to Include the whole of the embryo in a single GRN model such that every input to every part of RENEWAL The only way medical practice will advance beyond elegant forms of band aids and single molecule drug targets will be by interventions at the level of organization that life system actually operate, particularly the control systems. This Project concerns the most advanced example of genomic control systems biology we have at present. Its successful conclusion will show what the structure of these systems is; how to think about intervening in them; and directly inform considerations of the role of developmentally active regulatory gene mutations in the many forms of human developmental genetic disease we have become aware of. The medical research community is well aware of these points and the PI's of this application are frequently asked by forward looking members of it for collaborations, consultations, symposium presentations etc.