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

SysCODE：牙胚设计与工程（10 中的 2）

• 批准号: 7502025
• 负责人: RICHARD L MAAS
• 金额: $ 56.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502025
• 关键词: Address; Adult; Behavior; Biological; Cells; Clinical; Complex; Data; Dental; Dental Enamel; Development; Developmental Biology; Discipline; Effectiveness of Interventions; Embryo; Engineering; Epithelial; Epithelium; Extracellular Matrix; Gene Expression; Generations; Genetic; Genome; Genomics; Goals; In Vitro; Individual; Interdisciplinary Study; Jaw; Knowledge; Medicine; Mesenchymal; Mesenchyme; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Natural regeneration; Odontogenesis; Organ; Pathway interactions; Population; Property; Proteins; Proteome; Proteomics; Regulator Genes; Science; Series; Signal Pathway; Signal Transduction; Solutions; Staging; Stem cells; Structure; Sum; System; Time; Tissue Engineering; Tissues; Tooth Germ; Tooth structure; base; computerized tools; design; engineering design; high throughput screening; in vivo; loss of function; mutant

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.

发育生物学、计算和基因组科学以及组织工程的最新进展 使得考虑哺乳动物器官的再生成为可能。知识的整合 现在可以研究各个不同领域的各个组成部分如何在全球范围内组合 产生特定的生物结构和功能。这种基于系统的应用 解决牙齿工程问题的方法将使追求理性而非经验成为可能 在体外制造具有适当分化的牙釉质牙齿的策略。由于目前的知识 涉及牙发生的遗传途径及其临床可及性，牙齿代表了理想的牙齿 SysCODE 联盟的目标器官。像许多哺乳动物器官一样，牙齿是通过共同的方式形成的 涉及相互作用之间顺序、有序的信号交换的发展机制 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 通过整合不同的科学知识，网络可以在遗传和最终分子水平上得到解决 学科，并且这些信息可以以分子蓝图的形式使用来设计和构建 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，我们将生成一个动态时间 相互作用的上皮细胞和间充质细胞的一系列空间解析基因表达列表 调节早期牙齿形态发生的人群。这些分析将扩大到包括选择 小鼠突变体、丰富 ECM 蛋白的有限蛋白质组数据（w/项目 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为分子 早期牙齿发育的蓝图。这将涉及规范信号的识别和排序 牙上皮和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，我们将采用组织工程平台 结合分子蓝图和工程设计原理在项目 7 和 9 中开发 在体外指导牙齿发育。总之，该项目有潜力为如何提供一个范例 跨学科研究可以解决具有重大影响的问题，其解决方案可以改变医学。