MSM: CR Multiscale analysis of epithelial patterning: m*

描述（由申请人提供）： 胚胎发育本质上是一种多尺度现象，需要从基因到蛋白质，到细胞，到组织，最终到整个生物体的所有生物组织水平的高度协调过程。因此，多尺度方法对于理解发展机制是必不可少的。本项目提出将联合收割机实验和建模相结合，以研究表皮生长因子受体（EGFR）对发育中的上皮细胞进行模式化的机制，EGFR是从蠕虫到人类的动物组织的进化保守调节因子。使用果蝇作为实验系统，PI将量化EGFR信号的转录反应，开发EGFR介导的上皮层细胞通讯模型，并使用这些模型分析果蝇卵子发生中的EGFR系统，从基因到器官。这些实验将结合联合收割机发育遗传学、基因组学和转录分析实验。计算方法将包括渐近，均匀化和模型简化技术。这项综合性研究将导致第一个实验验证的模型EGFR信号在组织中。这项工作的成功依赖于PI在实验室实验、建模和跨发展尺度分析方面的综合专业知识。EGFR是正常组织发育所必需的，但EGFR信号转导失调与许多疾病有关，包括许多类型的人类癌症。因此，对EGFR在组织中作用的综合理解与广泛的医学问题直接相关。除了解决细胞命运多样化的发展中的基本问题，这项工作将导致计算和数据集成工具，为广泛的上皮图案问题。首先，PI将开发虚拟上皮细胞（VE），这是一种用于上皮图案系统计算分析的公开软件。第二，研究所将开发并公开提供果蝇卵子发生数据库（DODO），该数据库将联合收割机将其实验产生的异质数据集与生物信息学和生物统计学工具相结合。VE将使系统的建模和探索的时空动态细胞通信的扩散化学信号。DODO将补充现有的胚胎基因表达模式数据库，并形成一个起点，在大量的发育环境中的上皮模式的多尺度分析。该项目将汇集生物学，工程学和数学的研究人员，开展跨学科研究计划，旨在对EGFR系统产生新的认识。

DESCRIPTION (provided by applicant): Embryonic development is an intrinsically multiscale phenomenon that requires a highly coordinated processes at all levels of biological organization, from genes, to proteins, to cells, to tissues and, eventually, to the whole organism. Thus, multiscale approaches are indispensable for understanding the mechanisms responsible for development. This project proposes to combine experiments and modeling to study the mechanisms by which developing epithelia are patterned by the Epidermal Growth Factor Receptor (EGFR), an evolutionary conserved regulator of tissues in animals from worms to humans. Using Drosophila melanogaster as the experimental system, the PIs will quantify the transcriptional response to EGFR signaling, develop models of EGFR-mediated cell communication in epithelial layers, and use these models to analyze the EGFR system in Drosophila oogenesis, spanning the scales from genes to organs. The experiments will combine developmental genetics, genomics, and transcriptional profiling experiments. The computational approaches will include asymptotic, homogenization, and model reduction techniques. This integrative research will lead to the first experimentally validated model of EGFR signaling in tissues. The success of this effort relies on the combined expertise of the PI at bench experiments, modeling, and analysis across developmental scales. EGFR is essential for normal tissue development, but deregulated EGFR signaling has been associated with numerous diseases, including many types of human cancers. Hence, an integrative understanding of EGFR action in tissues is of direct relevance to a wide range of medical problems. In addition to addressing the fundamental questions of cell fate diversification in development, this work will lead to computational and data integration tools for a wide range of epithelial patterning problems. First, the PIs will develop Virtual Epithelium (VE), a publicly available software for the computational analysis of epithelial patterning systems. Second, the PIs will develop and make publicly available the Database of Drosophila Oogenesis (DODO) that will combine the heterogeneous datasets generated by their experiments with bioinformatics and biostatistics tools. VE will enable systematic modeling and exploration of the spatiotemporal dynamics of cell communication by diffusible chemical signals. DODO will complement the existing database of gene expression patterns in the embryo and form a starting point for a multiscale analysis of epithelial patterning in a large number of developmental contexts. The project will bring together researchers in biology, engineering and mathematics in an interdisciplinary research program aimed at bringing about new understanding of EGFR system.