MSM: CR Multiscale analysis of epithelial patterning: m*

MSM：CR 上皮图案的多尺度分析：m*

• 批准号: 7104893
• 负责人: Stanislav Y. Shvartsman
• 金额: $ 22.45万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104893
• 关键词: Drosophilidae; biochemical evolution; biological signal transduction; developmental genetics; disease /disorder model; embryogenesis; epidermal growth factor; epithelium; genetic transcription; genome; growth factor receptors; model design /development; oogenesis

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.

描述（由申请人提供）： 胚胎发育是一种本质上的多尺度现象，需要在各个级别的生物组织中进行高度协调的过程，从基因到蛋白质，细胞再到细胞，组织，最终再到整个生物体。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结合起来，以研究表皮生长因子受体（EGFR）形成的发育上皮的机制，表皮生长因子受体（EGFR）是一种从蠕虫到人类的动物组织的进化保守调节剂。 PI使用果蝇Melanogaster作为实验系统，将量化对EGFR信号传导的转录响应，开发上皮层中EGFR介导的细胞通信模型，并使用这些模型分析果蝇中的EGFR系统，从而跨越了从基因到Organs的鳞片。这些实验将结合发育遗传学，基因组学和转录分析实验。计算方法将包括渐进式，均质化和模型还原技术。这项综合研究将导致组织中EGFR信号传导的第一个实验验证的模型。这项工作的成功依赖于跨发育量表的基准实验，建模和分析的PI的综合专业知识。 EGFR对于正常组织的发育至关重要，但是EGFR信号传导与许多疾病有关，包括许多类型的人类癌症。因此，对组织中EGFR作用的综合理解与广泛的医疗问题是直接相关的。除了解决开发中细胞命运多样化的基本问题外，这项工作还将为各种上皮模式问题提供计算和数据集成工具。首先，PI将开发虚拟上皮（VE），这是用于上皮模式系统计算分析的公开软件。其次，PIS将开发并公开提供果蝇的数据库（Dodo），该数据库将结合其实验与生物信息学和生物统计学工具所产生的异质数据集。 VE将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将补充胚胎中基因表达模式的现有数据库，并在大量发育环境中对上皮图案进行多尺度分析的起点。该项目将在一个跨学科研究计划中汇集生物学，工程和数学研究人员，旨在使对EGFR系统有了新的了解。