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 使我们有可能设想哺乳动物器官的再生。知识的整合 从这些不同的领域，现在可以研究如何在全球范围内的各个组成部分结合联合收割机 以产生特定的生物结构和功能。这种基于系统的应用 牙体工程问题的解决将使人们从经验性的探索转向理性的探索 策略，以制造一个适当的分化，釉质轴承牙齿在体外。由于目前对 牙齿发育中的遗传途径及其临床可及性，牙齿代表了一种理想的 SysCODE联盟的目标器官像许多哺乳动物的器官一样，牙齿是通过一个共同的 一种发展机制，涉及相互作用之间的顺序，有序的信号交换 上皮和间充质细胞群。我们假设这种复杂的、动态的调节机制 网络可以在遗传和最终分子水平上解决，通过整合不同的科学方法， 这些信息可以以分子蓝图的形式用于设计和构建一个 牙.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选择 小鼠突变体，丰富ECM蛋白质的有限蛋白质组学数据（w/ Project 5），以及微机械 设计原则（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到分子 早期牙齿发育的蓝图这将涉及规范信号的识别和排序 牙上皮细胞与间充质细胞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则，在项目7和9中开发了 在体外指导牙齿发育。总而言之，本项目有可能提供一个范例， 跨学科研究可以解决一个影响力很大的问题，其解决方案可以改变医学。