MSM: CR Multiscale analysis of epithelial patterning: m*

描述(由申请人提供)： 胚胎发育是一种内在的多尺度现象，需要在生物组织的各个层面上高度协调地进行，从基因到蛋白质，再到细胞，再到组织，最终到达整个有机体。因此，多尺度方法对于理解负责发展的机制是必不可少的。该项目建议将实验和建模相结合，以研究表皮生长因子受体(EGFR)对发育中的上皮细胞形成模式的机制，EGFR是从蠕虫到人类的动物组织中的一种进化保守调节因子。以果蝇为实验系统，PI将对EGFR信号的转录反应进行量化，建立EGFR介导的上皮细胞通讯模型，并利用这些模型分析果蝇卵子发生中的EGFR系统，跨越从基因到器官的尺度。这些实验将结合发育遗传学、基因组学和转录图谱实验。计算方法将包括渐近化、齐次化和模型简化技术。这项综合性研究将导致第一个在组织中验证EGFR信号的实验模型。这项工作的成功依赖于PI在实验室实验、建模和开发规模分析方面的综合专业知识。EGFR对正常的组织发育是必不可少的，但EGFR信号失控与许多疾病有关，包括许多类型的人类癌症。因此，全面了解EGFR在组织中的作用与广泛的医学问题直接相关。除了解决发育中细胞命运多样化的基本问题外，这项工作还将导致针对广泛的上皮图案化问题的计算和数据集成工具。首先，PI将开发虚拟上皮(VE)，这是一个公开可用的软件，用于计算分析上皮图案系统。其次，PIS将开发并公开提供果蝇卵子发生数据库(DODO)，该数据库将把他们的实验产生的不同种类的数据集与生物信息学和生物统计学工具结合起来。VE将能够通过可扩散的化学信号对细胞通信的时空动力学进行系统的建模和探索。Dodo将补充胚胎中现有的基因表达模式数据库，并形成一个起点，用于对大量发育背景下的上皮模式进行多尺度分析。该项目将把生物学、工程学和数学领域的研究人员聚集在一起，开展一项跨学科研究计划，旨在对EGFR系统产生新的理解。

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.