National Center: Multiscale Analysis of Genomic and Cellular Networks (MAGNet)

在本文件中，我们概述了我们的建议，更新我们的中心多尺度分析遗传 网络（MAGNet）。在上一个供资期（2005 - 2010年），磁网中心在以下方面取得了重大进展： 描述涉及蛋白质和DNA的分子相互作用，在它们的功能分析中， 细胞环境，并利用这些信息来阐明控制生理和 病理表型如本提案所述，磁网有着令人信服的出版记录， 在生物学和疾病相关过程的多个尺度上取得了重要发现， 开发了被生物医学研究广泛采用的关键算法、模型和软件 社区 我们现在计划在多个领域从根本上新的研究方向，同时，实现全面的 整合我们的核心结构生物学和系统生物学主题。事实上，正如提案中所讨论的那样， 这些主题是高度协同的，结合起来可以帮助剖析原子水平之间的关系， 变化（遗传变异性）和细胞变化（表型变异性），明显适用于 阐明人类疾病的因果机制。中心的活动将涉及一个重要的， 多学科的努力，将解决多尺度问题，从蛋白质的原子级建模 相互作用特异性，多层调控网络的逆向工程，使用这些模型 解释遗传变异在决定细胞表型中的作用。这些活动将 直接影响三个驱动生物项目，旨在（a）研究关键的DNA结合特异性， 发育转录因子（Hox蛋白），（B）在致癌基因中模拟Erb B信号通路 使用多因子数据的背景和（c）组装第一个体内，全基因组，调控网络， 前列腺癌使用来自人类异种移植物的化学扰动的分子谱。 在追求卓越科学传统的同时，该中心将继续在 传播其研究人员开发的工具、模型、数据和算法。这将是 主要通过MAGNet的综合生物信息学平台george完成， 成熟成为一个非常引人注目和大量使用的工具，正如它的认可，由caBIG和其 与其他领先的软件工具，如GenePattern，Cytoscape和Bioconductor集成。磁体将 在我们先进数据中心的持续发展中也发挥着关键作用， 研究人员可以使用独特的计算设施，从而促进研究的重大进展 否则无法解决的问题。 通过MAGNet，我们将进一步改进和扩大在以前的资助中开始的教育活动 期间，产生了一个真正的综合实验计算课程。我们还将探讨 传播中心成果和组织社区活动的各种选择， 现在非常成功的梦想和RECOMB系统生物学会议。最后，MAGNet发挥了 在哥伦比亚的计算生物学跨学科计划的发展中发挥核心作用 大学横跨两个校区和七个学术部门。我们相信，独特的研究 我们创建的环境可以作为计算生物学在所有领域全面整合的模型 生物医学研究。

In this document we outline our proposal for the renewal of our Center for the Multiscale Analysis of Genetic Networks (MAGNet). Over the last funding period ('05-'10), the MAGNet Center has made major progress in the description of molecular interactions involving proteins and DNA, in their functional analysis within specific cellular contexts, and in using this information to elucidate mechanisms controlling physiological and pathological phenotypes. As documented in this proposal, MAGNet has a compelling publication record, has made important discoveries across multiple scales of biological and disease related processes, and has developed key algorithms, models, and software that have been broadly adopted by the biomedical research community. We now plan fundamentally new research directions in multiple areas while, in parallel, achieving full integration of our core Structural Biology and Systems Biology themes. Indeed, as discussed in the proposal, these themes are highly synergistic and in combination can help dissect the relationship between atomic level changes (genetic variability) and cellular changes (phenotypic variability), with obvious applications to the elucidation of causal mechanisms in human disease. Center activities will involve a significant, multidisciplinary effort that will tackle multiscale problems, ranging from the atomic-level modeling of protein interaction specificity, to the reverse engineering of multi-layer regulatory networks, to using these models for the interpretation of the role of genetic variability in determining cellular phenotypes. These activities will directly impact three Driving Biological Projects aimed at (a) studying the DNA-binding specificity of key developmental transcription factors (Hox proteins), (b) modeling ErbB signaling pathways in oncogenic contexts using multi-factorial data and (c) assembling the first in vivo, genome-wide, regulatory network for prostate cancer using molecular profiles from chemical perturbation of human xenografts. While pursuing its tradition of scientific excellence, the center will continue to play a prominent role in the dissemination of the tools, models, data, and algorithms developed by its investigators. This will be accomplished primarily through geWorkbench, MAGNet's integrative bioinformatics platform, which has matured into a highly compelling and heavily used tool, as shown by its endorsement by caBIG and by its integration with other leading software tools such as GenePattern, Cytoscape, and Bioconductor. MAGNet will also play a key role in the continued development of our advanced data center, which provides our investigators with access to unique computational facilities and thus facilitates significant progress on research problems that would otherwise be inaccessible. Through MAGNet, we will further improve and extend the educational activities started in the previous funding period, which have produced a truly integrated experimental-computational curriculum. We will also explore a variety of options for dissemination of Center results and for the organization of community-based events, such as the now very successful DREAM and RECOMB Systems Biology conferences. Finally, MAGNet has played a central role in the development of an inter-disciplinary program in Computational Biology at Columbia University that spans two campuses and seven academic departments. We believe that the unique research environment we have created can serve as a model for the full integration of Computational Biology in all areas of biomedical research.