ITR:"Regulography"- Quantitative Reconstruction of Transcriptional Regulatory Networks

《调控学》-转录调控网络的定量重建James C.Liao，Vwani Roychowdhury，Chiara Sabatti，David Eisenberg，Fuyuhiko Tamanoi，加州大学洛杉矶分校的David Eisenberg，Fuyuhiko Tamanoi目标和任务：这个项目的目标是基于大量的基因表达数据(从DNA微阵列产生)和各种辅助信息约束下的调控模型，如蛋白质与DNA、其他蛋白质和RNA的相互作用，重建转录调控网络的隐藏结构和动态。该项目的最终成果将是一个综合的框架(包括方法学和所需的数据库)，用于推断转录网络结构和动力学，可用于确定受未知药物效应、有毒化合物挑战和突变干扰的信号转导途径。我们正在使用酿酒酵母作为真核生物的模型来验证我们的范例。为此，我们正在进行以下具体任务：(1)开发一个分析性的和基于信息技术的框架，以定量和动态地重建各种转型前的监管网络。这包括转录调节(由蛋白质-DNA和蛋白质-蛋白质相互作用控制)，以及信使核糖核酸的加工、运输和稳定性调节(由各种蛋白质-信使核糖核酸相互作用控制)。这项工作建立在一种名为网络组件分析的新的系统重构方法之上。(2)获取和组织蛋白质-DNA、蛋白质-蛋白质相互作用、蛋白质-RNA相互作用、mRNA稳定性和基因表达噪声的数据。(3)对(1)和(2)中提出的框架范式进行了实验验证。团队组织：这个项目的PI来自五个不同的领域：廖博士是化学/生化工程师，专门从事代谢工程和DNA微阵列分析；Roychowdrury博士是电气工程师/计算机科学家，专门从事网络和系统理论；Tamamoi博士是专门研究酵母遗传学的微生物学家；艾森伯格博士是著名的生物化学家/结晶学家，专门研究蛋白质结构、功能和蛋白质-蛋白质相互作用；Sabatti博士是专门从事遗传和微阵列分析的统计学家。广泛影响：除了这里提出的基础科学发现之外，我们正在开展以下与信息技术相关的活动：(1)作为加州大学洛杉矶分校跨学科生物信息学计划的一部分，我们计划开发一门关于细胞内调控网络的两部分课程(面向工程和生物领域的高水平本科生和初级研究生)。(2)我们将利用加州大学洛杉矶分校许多跨学科研究机构的组织基础设施(包括NSF理论和应用数学研究所、加州纳米科学研究所和细胞模拟空间探索研究所)来吸引本科生和研究生。(3)我们将把我们的实验和分析结果整合到一个动态数据库中，并将其提供给更大的社区，我们相信这将刺激和帮助更大规模的细胞内过程建模的研究工作，涉及全国的学术和商业机构。

"Regulography"- Quantitative Reconstruction of Transcriptional Regulatory NetworksJames C. Liao, Vwani Roychowdhury, Chiara Sabatti, David Eisenberg, Fuyuhiko Tamanoi, University of California, Los AngelesGoal and Tasks: The goal of this project is to reconstruct the hidden structure and dynamics of transcriptional regulatory networks based on massive gene expression data (generated from DNA microarray) and regulatory models under the constraints of various ancillary information, such as protein interactions with DNA, other proteins, and RNA. The ultimate outcome of the project will be an integrated framework (incorporating both methodology and the required databases) for deducing transcriptional network structure and dynamic, which can be applied to define the signal transduction pathways perturbed by unknown drug effects, toxic compound challenges, and mutations. We are using Saccharomyces cerevisiae as the model eukaryote for verification of our paradigm. Toward this end, we are pursuing the following specific tasks: (1) Develop an analytical and IT-based framework for quantitative and dynamic reconstructions of various pre-translational regulatory networks. This includes transcriptional regulation (as governed by protein-DNA and protein-protein interactions), and processing, transport, and stability regulation of mRNA (as governed by various protein-mRNA interactions). This work builds on a novel system-reconstruction methodology called Network Component Analysis. (2) Acquire and organize data for protein-DNA, protein-protein interaction, protein-RNA interactions, mRNA stability, and gene-expression noise. (3) Experimental verification of the paradigm of the framework developed in (1) and (2). (4) Disseminate the results through a composite "regulographic" database.Team Organization: The PIs of this project come from five different fields: Dr. Liao is a chemical/biochemical engineer specialized in metabolic engineering and DNA microarray analysis, Dr. Roychowdrury is an electrical engineer/computer scientist specialized in networks and systems theories, Dr. Tamamoi is a microbiologist specialized in yeast genetics, Dr. Eisenberg is a renowned biochemist/crystallographer specialized in protein structure, function, and protein-protein interactions, and Dr.Sabatti is a statistician specialized in genetic and microarray analyses.Broader Impact: In addition to the fundamental scientific discoveries proposed here, we are pursuing the following information technology related activities: (1) As part of the interdisciplinary bioinformatics program at UCLA, we plan to develop a two-part course on intracellular regulatory networks (targeted toward upper-level undergraduate students and beginning graduate students in both engineering and biological fields) . (2) We will leverage the organizational infrastructure of a number of interdisciplinary research institutes on UCLA campus (including, the NSF Institute for Pure and Applied Mathematics, the California Nano-Science Institute, and the Institute for Cell Mimetic Space Exploration) to attract both undergraduate and graduate minority students. (3) We will integrate our experimental and analytical results into a dynamic database, and make it available to the larger community, which we believe will spur and aid research efforts on intracellular process modeling at a much larger scale, involving academic and commercial institutions nation wide.