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

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"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.