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

在这份文件中，我们概述了我们关于更新我们的基因多尺度分析中心的建议 网络(磁铁)。在过去的筹资期间(‘05-’10)，磁铁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，在其特定的功能分析中 细胞环境，并利用这一信息来阐明控制生理和 病理表型。如本建议书所述，Magic有令人信服的出版记录， 在生物和疾病相关过程的多个范围内做出了重要发现，并已 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。 我们现在从根本上规划多个领域的新研究方向，同时，实现全面 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，结合在一起可以帮助剖析原子水平之间的关系 变化(遗传可变性)和细胞变化(表型可变性)，明显应用于 阐明人类疾病的致病机制。中心的活动将涉及重大的、 将解决多尺度问题的多学科努力，范围从蛋白质的原子级建模 对于多层监管网络的反向工程，将这些模型用于 解释遗传变异性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学项目，旨在(A)研究Key的DNA结合特异性 发育转录因子(HOX蛋白)，(B)在致癌过程中模拟ErbB信号通路 使用多因素数据和(C)组装第一个活体内、全基因组范围的调控网络 前列腺癌使用来自人类异种移植的化学扰动的分子图谱。 在追求卓越科学传统的同时，该中心将继续在 传播其调查人员开发的工具、模型、数据和算法。这将是 主要通过磁铁的综合生物信息学平台geWorkbench完成，该平台有 成熟为一个非常引人注目和大量使用的工具，这从caBIG和它的 与其他领先的软件工具集成，如GenePattern、Cytoscape和BioConductor。磁铁将会 在我们高级数据中心的持续发展中也发挥着关键作用，这为我们提供了 调查人员能够使用独特的计算设施，从而促进研究的重大进展 否则就无法解决的问题。 通过MAGO，我们将进一步完善和扩大在以前的资助中开始的教育活动 这一时期，产生了一个真正完整的实验-计算课程。我们还将探索一种 传播中心成果和组织以社区为基础的活动的各种选择，如 作为现在非常成功的梦想和RECOMB系统生物学会议。终于，磁石发挥了作用 在哥伦比亚大学计算生物学跨学科项目的发展中发挥核心作用 这所大学横跨两个校区和七个学术部门。我们相信这项独特的研究 我们创造的环境可以作为计算生物学在所有领域完全整合的模型 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.