Systematic Reconstruction of Epithelial-Mesenchymal Communication in Organ Development

项目摘要 间充质细胞是组织间质的主要成分，并且以其在支持组织间充质中的作用而闻名。 器官的物理结构。它们与上皮细胞并列并交流，以控制器官 在胚胎中的发育，并调节组织炎症，损伤修复和成年人的癌症进展。 传统上，不同器官中的间充质细胞被认为具有相似的功能。但最近的 研究已经揭示了来自骨髓间充质细胞的基因表达特征的意外多样性， 不同的器官这种多样性可能在调节间充质-上皮相互作用中起关键作用 从而影响器官发育和生理学。本提案的首要目标是了解如何 上皮-间充质相互作用控制不同器官的器官发生。为了实现这一目标，我们将 首先解决间充质多样性如何作为不同信号历史的结果而产生的问题。 我们将开发一种新型的高通量系统，同时测试数万种信号组合。 然后，我们将研究如何上皮间充质相互作用控制组织形态发生，通过重建 以及离体遗传干扰这种相互作用。我们特别感兴趣的是比较 和可塑性的上皮间质相互作用在不同的器官，并确定的作用， 上皮细胞和间充质细胞在控制形态发生中共享的细胞外基质。我们将 将实验测量与计算模型紧密结合，以产生定量框架 来理解器官形态发生。通过整合来自不同领域的工具和材料，我们将获得 对长期被忽视的发展起源和功能影响的基本理解 间充质细胞这些见解和工具将使类器官的工程能够更好地建模 发展和疾病，并将推动组织工程领域。

PROJECT SUMMARY Mesenchymal cells are major components of tissue stroma and best known for their role in supporting the physical structure of organs. They juxtapose to and communicate with epithelial cells, to control organ development in embryos, and to regulate tissue inflammation, injury repair and cancer progression in adults. Traditionally, mesenchymal cells in different organs were thought to perform similar functions. However, recent studies have revealed unexpected diversity of gene expression signatures among mesenchymal cells from different organs. Such diversity is likely to play a crucial role in regulating mesenchymal-epithelial interactions and thus organ development and physiology. The overarching goal of this proposal is to understand how epithelial-mesenchymal interactions control organogenesis across different organs. To achieve this goal, we will first address the question of how mesenchymal diversity arises as the consequence of distinct signaling histories. We will develop a novel high-throughput system to simultaneously test tens of thousands of signal combinations. We will then investigate how epithelial-mesenchymal interactions control tissue morphogenesis, by reconstituting and genetically perturbing such interactions ex vivo. We are especially interested in comparing the specificity and plasticity of epithelial-mesenchymal interactions across different organs, and identifying the role of extracellular matrices that are shared by epithelial and mesenchymal cells in controlling morphogenesis. We will closely integrate experimental measurements with computational models to produce a quantitative framework for understanding organ morphogenesis. By integrating tools and materials from diverse fields, we will gain a fundamental understanding about the developmental origin and functional implications of the long-overlooked mesenchymal cells. These insights and tools will enable the engineering of organoids to better model development and diseases, and will advance the field of tissue engineering.