IBCST - Competitive Renewal of MSM: Multiscale Studies of Segmentation in Verterb

描述(申请人提供)：本次竞争性续签是对5R01GM076692-01《脊椎动物胚胎分割多尺度研究》资助的成功工作(已发表的35篇论文)的扩展，以开发用于模拟鸡体节形成的多尺度模拟工具。当前提案的战略背景是将最初资助期间取得的多项成就统一到一个连贯的体细胞发生模型中，并交付2007年4月11日至12日由美国国立卫生研究院领导的机构间建模和分析小组(IMAG)小型研讨会和模型共享首席调查者会议的主要建议：“一个多尺度模拟技术的重点示范项目，它解决了发育生物学中明确定义的特定问题，包括在整个发育过程中具有重要意义的各种生物学机制，对此统一的多尺度方法是必不可少的。”鸡的体细胞发生是一个很好的示范项目的选择，因为它在实验上表现得很好，需要模拟最基本的发育机制，并且需要在多个尺度上统一现有的方法(在这种情况下，将广泛使用的用于亚细胞建模的开源软件包系统生物学工作台(SBW)和用于多细胞建模的CompuCell3D(CC3D)合并到一个组织模拟环境(TSE)中)，并开发一些在发育生物学模拟以及癌症和血管研究等关键生物医学领域中广泛有用的关键附加软件组件。该提案利用了NIGMS最近在1R01GM077138-01A1和1R01GM081070-01A1中分别对Glazier和Sauro进行的软件基础设施开发方面的投资，虽然这两项投资分别极大地扩大了CC3D和SBW的范围(通过支持改进的用户界面来生成、执行和分析模型；增强脚本语言支持、开发测试和验证模块、改进文档、培训材料和用户支持)，但不包括合并后的SBW/CC3D的开发或并行化，或部署具有生物意义的示范项目。公共卫生相关性：胚胎发育过程中细胞相互作用和潜在分子机制的模拟可以在实验生物医学研究中发挥重要作用，有助于解释实验结果，建议实验，预测实验结果，并导致对基本生物学机制的更深入理解，从而加快对疾病的理解和治疗策略的制定。本研究计划的成功完成将改善医疗机构和行业的参与，以及它们在开发建模工具和有效利用它们创造新药和治疗方法方面的相互作用。

DESCRIPTION (provided by applicant): This competitive renewal extends the successful work (35 published papers) funded under 5R01GM076692-01 Multiscale Studies of Segmentation in Vertebrate Embryos to develop multiscale simulation tools for the simulation of somite formation in chicken. The strategic context of the current proposal is to unify the multiple accomplishments achieved during the original funding period into a coherent model of somitogenesis and to deliver the primary recommendation of the NIH-led Interagency Modeling and Analysis Group (IMAG) Miniworkshop and Principal Investigator's Meeting on Model Sharing, April 11-12, 2007: "a focused demonstration project for multiscale simulation techniques, which addresses a well- defined, specific problem in developmental biology, which includes a variety of biological mechanisms of importance throughout development and for which a unified multiscale approach is essential." Chick somitogenesis is an excellent choice of demonstration project because it is well- characterized experimentally, requires simulation of most fundamental developmental mechanisms, and requires both the unification of existing methodologies at multiple scales (in this case merging the widely-employed, open-source software packages Systems Biology Workbench (SBW) for subcellular modeling and CompuCell3D (CC3D) for multicell modeling into a Tissue-Simulation Environment (TSE)) and the development of a number of key additional software components of broad utility in developmental-biology simulation and in critical biomedical areas such as cancer and vascular research. This proposal leverages the investment NIGMS has recently made in software infrastructure development under 1R01GM077138-01A1 to Glazier and 1R01GM081070-01A1 to Sauro, which, while they greatly increase the scope of CC3D and SBW separately (by supporting improved user interfaces for model generation, execution and analysis; enhanced scripting- language support, development of testing and validation modules, improving documentation, training materials and user support), do not cover the development or parallelization of a merged SBW/CC3D, or the deployment of a biologically-meaningful demonstration project. PUBLIC HEALTH RELEVANCE: Simulations of cell interactions and underlying molecular mechanisms during embryonic development can play a vital role in experimental biomedical research, help with the interpretation of experimental results, suggest experiments, predict experimental outcomes and lead to a deeper understanding of fundamental biological mechanisms, thus expediting the understanding of diseases and the development of treatment strategies. Successful completion of the presented research plan will improve the involvement of medical institutions and industry, and their interaction in the development of modeling tools and their effective use in the creation of novel drugs and treatments.