Egg to Embryo: Gene Regulatory Circuitry in Development

描述（由申请人提供）：这是一个计划项目的续期申请，现在已经14年了。在这里，我们建议在解决和验证基因调控网络（GRN）的发展方面取得的巨大成功的基础上，建立新的方向。GRNs在基因组调控密码方面为发育过程提供了因果解释，所有物种特异性发育过程最终都是在基因组调控密码中编程的。一个发展的GRN作为一个概念，系统级的逻辑图，我们已经证明，拥有直接的预测能力。因此，GRNs在具有调节意义的功能基因组DNA序列与胚胎发生和身体计划形成的生物学之间架起了桥梁。他们通过指定调节相互作用来实现这一点，这些相互作用因果地驱动不同细胞区域中调节状态的进展。近年来，该方案 一直负责最先进的发展GRN的实验解决方案，但可用于任何发展中的动物有机体。这是GRN潜在的海胆胚胎的内中胚层领土的规范。最近的证明的原则，作为一个GRN接近完成，它确实提供了解释所有观察到的生物，功能已经在这项工作中获得。我们现在打算利用我们已经开发的越来越多的成功的技术和概念方法来分析GRN，以应对迄今为止无法访问的挑战，甚至无法定义。目前或即将完成的海胆胚胎GRN包括胚胎的所有主要领域，但其中一个领域除外，从最早的合子基因组活动（在卵裂开始时）到原肠形成之前。此外，在本计划项目的本期， GRN已成功地构建了颅神经嵴的鸡使用的知识和技术方法，由该计划项目开创。 海胆胚胎GRN的戴维森组件（项目I）现在将扩展GRN分析，以将整个胚胎纳入单个GRN模型中，以便更新每个部分的每个输入。医疗实践将超越优雅形式的创可贴和单分子药物靶点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。该项目涉及我们目前拥有的最先进的基因组控制系统生物学的例子。它的成功结论将显示这些系统的结构是什么;如何考虑干预它们;并直接告知我们已经意识到的许多形式的人类发育遗传疾病中发育活性调节基因突变的作用。医学研究界非常了解这些要点，前瞻性成员经常要求本申请的PI进行合作、咨询、研讨会演示等。

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.