Developmental Mechanisms of Trachea-Esophageal Birth Defects

整合基因组学核心的目标是提供一个全面的，具有成本效益和高度集成的管道来分析和相互关联来自所有项目的基因组数据，并加速该计划。这个项目的所有组成部分都依赖于基因组分析。项目1将对患者-父母三人组进行全外显子组测序（WES），以确定可能导致ted的突变。项目2和项目3将确定HH、BMP、Gli2/3和Sox2在动物模型和hpsc衍生的TE类器官中的转录靶点，并确定这些途径如何在基因调控网络（GRN）中相互作用。通过整合来自每个项目的基因组数据和来自不同功能基因组数据库的信息，我们将注释来自项目1的候选患者变异，优先考虑在项目2和项目3中进行测试。最后，我们将对导致TE的突变进行建模，以确定它们如何破坏控制TE发展的GRN。总之，这将提供一个系统水平的理解基因型-表型基础的ted。因此，每一个项目，以及它们之间有效的信息流，都需要集成基因组学核心提供严格的计算、统计和信息学分析。我们已经组建了一个由哥伦比亚大学和CCHMC的基因组学和计算专家组成的团队，以创建一个具有协同作用的专业知识套件的核心，这在任何一个机构都不容易获得。这为整个项目提供了成本效益、最先进的支持，并促进了项目之间的协同作用，从而提高了生产率，加速了总体目标的实现。该中心由哥伦比亚基因组中心副主任沈博士和非洲爪鼠模式生物数据库Xenbase联合主任Zorn博士共同领导，前者是研究人类疾病遗传学的计算基因组学方法专家，后者是基因调控网络专家。

The aim of the Integrated Genomics Core is to provide a comprehensive, cost effective and highly integrated pipeline to analyze and inter-relate the genomic data from all of the projects and accelerate the program. All components of this Program Project rely of genomic analyzes. Project-1 will perform whole exome sequencing (WES) of patient-parent trios to identify putative TED-causing mutations. Project-2 and project-3 will identify the transcriptional targets of HH, BMP, Gli2/3 and Sox2 in animal models and hPSC-derived TE organoids and determine how these pathways interact in a gene regulatory network (GRN). By integrating genomic data from each of these projects with information from diverse functional genomic databases, we will annotate candidate patient variants from project-1, prioritizing those to test in projects-2 and -3. Finally we will model the TED­causing mutations to determine how they disrupt the GRN governing TE development. Together this will provide a systems level understanding of genotype-phenotype basis of TEDs. Thus, each of the projects, and the effective information flow between them, requires the rigorous computational, statistical and informatics analyses provided by the Integrated Genomics Core. We have assembled a team of genomics and computational specialists from Columbia and CCHMC to create a core with a synergistic suite of expertise not readily available at either institution. This provides cost effective, state-of-the-art, support for the entire program and facilitates synergy between the projects thus enhancing productivity and accelerating the overall goals. The core is jointly directed by Dr. Shen the Associate Director of the Columbia Genome Center, an expert computational genomics methods to study the genetics of human diseases, and Dr. Zorn at CCHMC, the co-Director of Xenbase, the Xenopus model organism database, who is an expert in gene regulatory networks. The aims of the core are: Aim 1 Analysis of WES and identification of candidate disease causing variants Aim 2 Analysis of RNA-seq and ChIP-seq data from animal models and human PSC-derived organoids. Aim 3 Data integrations to 1) elucidate GRN controlling normal and defective TE development and 2) prioritize candidate TED-causing mutations.