SysCODE: Tooth Germ Design and Engineering (2 of 10)

发育生物学、计算和基因组科学以及组织工程的最新进展 使研究哺乳动物器官的再生成为可能。知识的整合 来自这些完全不同的领域，现在能够研究单个组件如何在全球范围内组合 产生特定的生物结构和功能。以此为应用基础的系统 对牙齿工程问题的探讨将使人们有可能追求理性而不是经验主义 体外构建分化良好的牙釉质承载牙的策略。由于目前对 参与牙齿发育的遗传途径及其临床可及性，牙齿代表了一个理想的 SysCODE联盟的目标器官。像许多哺乳动物的器官一样，牙齿是通过共同的 一种发育机制，涉及相互作用之间信号的顺序、有序交换 上皮细胞和间充质细胞群。我们假设这种复杂的、动态的监管 网络可以通过不同科学的整合在基因和最终的分子水平上得到解决 这些信息可以以分子蓝图的形式用于设计和构建 牙齿。为了实现这一目标，我们提出了三个具体目标。在目标1中，我们将生成动态时间 相互作用的上皮细胞和间充质细胞的一系列空间分辨基因表达列表 调节早期牙齿形态发生的种群。这些分析将扩大到包括精选 小鼠突变体，丰富的ECM蛋白的有限蛋白质组数据(w/Project 5)，以及微机械 设计原则(带项目6)。在目标2中，我们将与SysCODE计算团队合作， 将这些信息合成到基因调控网络(GRN)中，并与其他数据一起合成分子 牙齿早期发育蓝图。这将涉及规范信令的识别和排序 牙上皮与间充质之间的通路及转录调控网络分析 使用新的基因组和计算工具。最后，在目标3中，我们将使用组织工程平台 在项目7和9中结合分子蓝图和工程设计原则进行开发 来指导牙齿的体外发育。总之，这个项目有可能提供一个范例，说明如何 跨学科研究可以解决一个影响很大的问题，其解决方案可以改变医学。

Recent advances in developmental biology, computational and genome science, and tissue engineering have made it possible to contemplate the regeneration of mammalian organs. The integration of knowledge from these disparate fields now enables the study of how individual components combine on a global scale to generate particular biological structures and functions. The application of such a systems-based approach to the problem of tooth engineering will make it possible to pursue rational rather than empiric strategies to fabricate a properly differentiated, enamel bearing tooth in vitro. Owing to current knowledge of the genetic pathways involved in odontogenesis and its clinical accessibility, the tooth represents an ideal target organ for the SysCODE Consortium. Like many mammalian organs, the tooth forms via a common developmental mechanism that involves the sequential, ordered exchange of signals between interacting epithelial and mesenchymal cell populations. We hypothesize that this complex, dynamic regulatory network can be resolved at the genetic and ultimately molecular level by the integration of different scientific disciplines and that this information can be used in the form of a molecular blueprint to design and build a tooth. To accomplish this goal, we propose three Specific Aims. In Aim 1, we will generate a dynamic time series of spatially resolved gene expression lists for the interacting epithelial and the mesenchymal cell populations that regulate early tooth morphogenesis. These analyses will be expanded to include select mouse mutants, limited proteomic data for abundant ECM proteins (w/ Project 5), and micromechanical design principles (w/ Project 6). In Aim 2, in conjunction with the SysCODE Computational Team, we will synthesize this information into a gene regulatory network (GRN), and with other data, into a molecular blueprint for early tooth development. This will involve the identification and ordering of canonical signaling pathways between dental epithelium and mesenchyme and analysis of transcriptional regulatory networks using new genomic and computational tools. Lastly, in Aim 3, we will employ tissue engineering platforms developed in Projects 7 and 9 in conjunction with the molecular blueprint and engineering design principles to direct tooth development in vitro. In sum, this Project has the potential to provide a paradigm for how interdisciplinary research can address a high impact problem whose solution can transform medicine.