Subramaniam Shankar, Professor
University Of California San Diegocity: La Jolla country: United States (us)
Grant 5R01GM078005-06 from National Institute Of General Medical Sciences
Abstract: This proposal addresses the continued support for maintenance and further development of the UCSD- Nature Signaling Gateway. The Signaling Gateway (http//www.signaling-gateway.org)is a collaboration between the University of California, San Diego and Nature Publishing Group (NPG) and is designed to facilitate navigation of the complex world of cell signaling research. The Signaling Gateway comprises three components the Molecule Pages (MP), the Signaling Update and the Data Center. The Data Center is a legacy of the Alliance for Cellular Signaling and will merely be maintained at status quo. The Signaling Update, which provides short editorial highlights of recent signaling papers, a library of relevant publications, a conference calendar, and pertinent news stories, will continue to be updated on a weekly basis with fresh editorial content. The MPs provide regularly updated, essential information derived from public databases and sequence analysis on approximately 4000 mammalian proteins involved in signal transduction. In addition, 500 of these MPs contain published, expert-authored information about the protein. Published MPs contain both a full-text review article about the molecule and highly structured data for bioinformatics interrogation, including information on protein-protein and protein-ligand interactions, subcellular localization, post-translational modifications and biological or enzymatic activity. Importantly, NPG administers rigorous peer and editorial review of each published MP. The MP data are stored in an object-relational database format and are freely accessible to the authors, the reviewers and the public via a web interface that serves as a presentation layer. The MPs, Signaling Update and Data Center are routinely accessed by tens of thousands of members of the signal transduction community, both abroad and in the US, and remain a highly trusted and valuable resource for cell signaling researchers. In addition to providing continued maintenance for the Signaling Gateway, this proposal aims to expand the MPs to other species, publish updated versions of existing MPs, develop novel microRNA MPs, create complex query interfaces, introduce a new and interactive MP Wiki, and provide the ability to export an MP and its contents to other public repositories and to the larger user community
Keywords: Academia; Address; Antibodies; Apoptosis; Archives; Area; base; Biochemical; Biochemical Pathway; Biochemical Process; Bioinformatics; Biological; Biological Assay; Biological databases; Biological Process; Biomedical Research; Breathing; Calendar; California; Cataloging; Catalogs; Categories; Cells; Collaborations; Collection; Communities; Complement; Complex; Computer software; Custom; Data; data management; Data Sources; Databases; design; Development; Differentiation and Growth; digital; editorial; Electronic Mail; Ensure; Environment; Event; Extensible Markup Language; falls; Functional RNA; Funding; Genetic; Glues; Grant; Housing; Human; Individual; innovation; Institution; Internet; Investigation; Knowledge; Laboratories; Libraries; Ligands; Link; Literature; Maintenance; Maps; Mediating; member; MicroRNAs; Mining; Minor; Molecular; Monitor; Mus; National Institute of General Medical Sciences; Nature; news; novel; Nucleotides; Output; Pan Genus; Paper; Pathway interactions; peer; Peer Review; Phenotype; Physiological; Post-Translational Protein Processing; Process; Program Development; Property; protein function; protein protein interaction; Proteins; Proteome; Proteomics; Protocols documentation; Publications; Publishing; Publishing Peer Reviews; rapid growth; Rattus; Reader; Reagent; Regulation; relational database; Reporter; Reporting; repository; Research; Research Personnel; Resources; response; RNA; Role; Science; Sequence Analysis; Services; Signal Transduction; Signaling Molecule; Signaling Protein; Software Engineering; Source; Stimulus; Structure; supercomputer; symposium; System; Systems Biology; Techniques; Text; Tissues; tool; trafficking; Translating; Translational Regulation; Trust; Universities; Update; user-friendly; web interface; web site; wiki; Work; Writing
Relevance: Normal and pathophysiological function is controlled by biochemical processes in cells and tissues. Cellular responses to stimuli, including growth, differentiation, arrest and apoptosis are a consequence of cellular signaling and regulatory events. The Signaling Gateway is a project that captures our state-of- the-art knowledge of the signaling machinery; namely, the proteome that composes the molecular pathways that mediate defined physiological phenotypes. This project represents collaboration between an academic institution and a reputable publishing group and aims to create an expert-curated, peer- reviewed catalog of all mammalian signaling molecules and the myriad biological and biochemical pathways in which they participate. The Signaling Gateway, which is already widely used by the biomedical research community, will be expanded in scope to include the latest material on signaling proteins, an annotated database and expert-authored reviews of micro RNA molecules, an efficient query system and an ability to export the information in biologist-friendly as well as machine-readable formats. Most importantly, we propose to engage the larger biomedical research community in the rapid dissemination of new signaling-related techniques, reagents and data via a Wiki mechanism
Project start date: 2006-09-30
Project end date: 2013-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-07-344
5R01GM078005-06 (2011): $557081
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Subramaniam Shankar
MICRORNA IN FUNCTIONAL REGULATION OF ENDOTHELIAL CELLS IN RESPONSE TO FLOW
Subramaniam Shankar, University Professor
University Of California San Diegocity: La Jolla country: United States (us)
Grant 1R01HL106579-01 from National Heart, Lung, And Blood Institute
Abstract: MicroRNAs (miRs) are small non-coding RNAs that play crucial roles in regulating mRNA stability and translational repression. There is increasing evidence that miRs can modulate gene expression in the cardiovascular system. Endothelial cells (ECs) lining the vascular lumen are sensitive to mechanical factors such as fluid shear stress. During the past two decades, this research team has worked on the mechanisms of mechanotransduction in ECs and the consequent gene expression. The results from them and others indicate that steady and pulsatile shear stresses (PS) with a net forward direction are anti-atherogenic by inducing genes involved in anti-proliferation and anti-inflammation. In contrast, oscillatory shear stress (OS) without a significant forward direction is pro-atherogenic by activating pro-proiferative and pro-inflammatory genes. Based on new evidence in the literature and our recent findings that miRs play an important role in regulating EC genes, we hypothesize that anti-atherogenic (PS) and pro-atherogenic (OS) flow patterns induce distinct patterns of miRs, and hence the differential gene expressions and functional consequences. We will use in vitro, in vivo, and in silico approaches to develop an integrated system to elucidate the roles of miRs in regulating EC functions in response to different flow patterns. This multi-P.I. research project, by combining experimental data obtained from cultured ECs and mouse models with molecular, genomics and systems approaches, will elucidate the mechanisms of functional regulation by miRs in ECs under flows. In order to test our hypothesis, we propose the following five specific aims (1) to establish miR expression profiles in cultured ECs in response to PS vs. OS. (2) To determine the target mRNAs of miRs in response to PS vs. OS. (3) To decipher the functional gene expression profiles regulated by miRs under PS vs. OS. (4) To elucidate the functional consequences of miR regulation under PS vs. OS. (5) To verify the role of miRs in functional regulation of vascular ECs exposed to different flow patterns in vivo. In this proposal the role of miR in regulating vascular functions will be studied under different flow patterns with a combination of experimental and computational approaches to perform multi-scale analyses from miRs/mRNAs to cellular functions. This innovative, multidisciplinary project includes (a) comprehensive genome-wide approaches to establish the miR profiles in ECs, (b) CLIP-seq approaches to elucidate the interactions between miRs and target mRNAs, (c) systems biology approaches to map the functional gene expression and biological consequence regulated by miRs, and (d) in vivo approaches in lesion-induction mice to validate the roles of miRs under different flow patterns established in vitro. The results will enhance the mechanistic insights of the roles of mechano- regulation and functional genomics at the systems biology level and may contribute to the development of novel approaches for the diagnosis and treatment of cardiovascular diseases. MicroRNAs (miRs) are small non-coding RNAs that play crucial roles in the regulation of mRNA stability and translational repression, leading to the modulation of ~30% of the human genome. We will use in vitro, in vivo, and in silico technologies to develop an integrated systems approach to elucidate the roles of miRs in regulating endothelial functions in normal and pathophysiological flow conditions. The result may and may contribute to the development of novel approaches for the diagnosis and treatment of cardiovascular diseases
Keywords: Analysis, Data; Animals; Anti-atherogenic; Antiatherogenic; aortic arch; Aortic arch structure; Apo-E; ApoE; APOE [{C0003595}]; Apolipoprotein E; Apoptosis; Apoptosis Pathway; Arch of the Aorta; Arch, Aortic; Area; Arterial Fatty Streak; Atheroma; Atheromatous; Atheromatous degeneration; Atheromatous plaque; atherosclerosis plaque; atherosclerotic lesions; atherosclerotic plaque; base; Bio-Informatics; Bioavailability; bioavailability of drug; Bioinformatics; Biologic Availability; Biological; Biological Availability; Biology; Biomechanics; Blood flow; Blood Vessels; Cardiovascular; Cardiovascular Body System; Cardiovascular Diseases; cardiovascular disorder; Cardiovascular system; Cardiovascular system (all sites); cDNA Arrays; cDNA Microarray; Cell Death, Programmed; Cell Function; Cell Line; Cell Lines, Strains; Cell physiology; Cell Process; CellLine; Cellular Function; Cellular Physiology; Cellular Process; Chemotaxis, Leukocyte; circulatory system; Complex; computational modeling; computational models; computational simulation; computer based models; Computer Simulation; computerized modeling; Computerized Models; computerized simulation; cross-link; crosslink; Crossmatching, Tissue; cultured cell line; Data; Data Analyses; Development; Diagnosis; Differential Gene Expression; Endothelial Cells; Endothelium; Event; experiment; experimental research; experimental study; Expression Profiling; Expression Signature; fluid; functional genomics; Functional RNA; Gene Expression; Gene Expression Profile; gene expression signature; gene function; gene product; Genes; genome-wide; Genomics; Histocompatibility Testing; histocompatibility typing; Human Genome; Immune Precipitation; Immunoprecipitation; in silico; In Vitro; in vivo; Inflammation; Inflammatory; INFLM; innovate; innovation; innovative; insight; Lesion; Leukocyte Chemotaxis; Leukotaxis; liquid; Liquid substance; Literature; loss of function; Maintenance; Maintenances; Mammals, Mice; Maps; Mathematical Model Simulation; Mathematical Models and Simulations; Mechanics; Messenger RNA; Mice; Micro RNA; MicroRNAs; miRNA; Modeling; Models, Computer; Modification; molecuar profile; Molecular; Molecular Fingerprinting; Molecular Profiling; molecular signature; mouse model; mRNA; mRNA Stability; multidisciplinary; Murine; Mus; new approaches; Non-Coding; Non-Coding RNA; novel approaches; novel strategies; novel strategy; Organ System, Cardiovascular; pathway; Pathway interactions; Pattern; Phenotype; Physiologic Availability; Play; protein expression; Proteins; public health relevance; R01 Mechanism; R01 Program; Regulation; Research; Research Grants; Research Project Grants; Research Projects; Research Projects, R-Series; research study; response; RNA, Messenger; Role; RPG; shear stress; Simulation, Computer based; social role; Streaks, Arterial Fatty; Subcellular Process; System; System, LOINC Axis 4; Systems Biology; Technology; Testing; Thoracic aorta; Tissue Crossmatchings; Tissue Typing; Tissue-Specific Differential Gene Expression; Tissue-Specific Gene Expression; transcriptome; Translational Inhibition; Translational Repression; Trees; vascular; Vascular Endothelial Cell; Vascular, Heart; virtual simulation; vulnerable plaque; Work
Relevance: MicroRNAs (miRs) are small non-coding RNAs that play crucial roles in the regulation of mRNA stability and translational repression, leading to the modulation of ~30% of the human genome. We will use in vitro, in vivo, and in silico technologies to develop an integrated systems approach to elucidate the roles of miRs in regulating endothelial functions in normal and pathophysiological flow conditions. The result may and may contribute to the development of novel approaches for the diagnosis and treatment of cardiovascular diseases
Project start date: 2011-01-01
Project end date: 2014-11-30
Budget start date: 1-JAN-2011
Budget end date: 30-NOV-2011
PFA/PA: PA-10-067
1R01HL106579-01 (2011): $732279
3R01HL106579-01S1 (2011): $41360
Subramaniam Shankar, Professor
University Of California San Diegocity: La Jolla country: United States (us)
Abstract: BRIDGE A LIPID MAPS NETWORKS The main objective of this Bridge Project is the reconstruction and modeling of lipidomic networks in macrophages. In the first part of this objective, a combination of inference and statistical learning based methods will be used to reconstruct networks from lipid and gene expression data obtained by the Lipidomics Core laboratories of LIPID MAPS. The statistical learning approach includes use of principal component regression and temporal analysis of modules. The LIPID MAPS project will also carry out experiments with stable isotope metabolite precursors. These include CIS-labeled arachidonate, acetate, palmitate, and mevalonate. Bridge A will develop quantitative methods for modeling and analysis of isotopomeric data and will provide kinetic analyses of derived models. From the latter developments, it will be possible to design novel experiments and conceive quantitative hypotheses to predict the consequences of pharmacological and genetic perturbations on lipid networks. In addition, the isotopomer data will be used to elucidate pathways of catabolism versus anabolism of lipids. Unlike protein networks, little is known about the lipid networks of mammalian cells. Development of lipid networks requires a systems biology approach involving large scale measurements of network players followed by mathematically intensive integrative analyses of the data to develop interaction models. These models serve as frameworks for understanding cellular function in normal and pathological conditions. Bridge A will lead the development of new methods for reconstruction and modeling of lipid networks and will provide the scientific community with tools for pathway-based approaches to study cellular function
Keywords: Acetates; Anabolism; arachidonate; base; Catabolism; Cell physiology; Communities; Data; Data Analyses; design; Development; Gene Expression; Genes; Genetic; Kinetics; Label; Laboratories; Lead; Lipid A; Lipids; Machine Learning; macrophage; Mammalian Cell; Maps; Mass Spectrum Analysis; Measurement; Metabolic; Metabolic Pathway; Methods; mevalonate; Modeling; novel; Online Systems; Palmitates; Pathway interactions; pathway tools; Proteins; Protocols documentation; reconstruction; Recycling; research study; stable isotope; Structure; Systems Biology
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5U54GM069338-09_0001 (2011): $470070
BIOINFORMATICS AND DATA COORDINATION
Subramaniam Shankar, Professor
University Of California San Diegocity: La Jolla country: United States (us)
Abstract: A comprehensive understanding of lipidomic networks is essential before models of cells in normal and pathological conditions can be developed. The LIPID MAPS project generates large amounts of data on lipid metabolites and genes to quantitatively study macrophage lipid networks under normal and diseased conditions. This exemplar catalog of mammalian lipids will be of immense value to the community. The primary objective of Core B will be to coordinate the data and knowledge from LIPID MAPS project and disseminate it to the larger research community. Achieving this objective involves continued development of complex multi-tier informatics and computational infrastructure, including databases, applications, and interfaces. In the second phase of LIPID MAPS, we will build infrastructure for the management of data arising from measurements of lipids in macrophages isolated from animal models. To facilitate analysis of the data by the Lipidomic Core laboratories, a biologist-friendly statistics workbench will be developed. The major focus of Core C is Bioinformatics and Systems Biology of Lipidomic networks. The specific objectives include statistical analysis of data to decipher regulation of lipids under normal and pathological conditions, reconstruction of lipidomic networks, development of mechanisms and hypotheses of lipid modules involved in pathology, and quantitative analysis of lipids in a context-specific manner. The approaches to be taken include use of statistical methods such as analysis of variance, statistical learning, and mathematical methods that model lipidomic networks. The new strategies will also include development of methods to analyze gene expression changes to identify coordinately regulated genes and pathways and the study of fluxes of lipids through metabolic networks. Modeling the influences of genetic and pharmacological perturbations will form another aspect of the proposed work. The LIPID MAPS web resource is the first of its kind and provides a comprehensive list of mammalian lipids along with quantitative metrics (standards) and context-specific cellular networks of lipids. The Bioinformatics and Data Coordination Core will develop databases, tools, and interfaces to facilitate public use of this valuable resource
Keywords: Acetates; Anabolism; Analysis of Variance; Animal Model; Biochemical Pathway; Bioinformatics; Cataloging; Catalogs; Cell model; Communities; Complex; computer infrastructure; Data; Data Analyses; data management; Databases; Development; Disease model; Disease Pathway; Experimental Designs; Fingerprint; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Informatics; Information Dissemination; Internet; Knowledge; Label; Laboratories; Lipids; Machine Learning; macrophage; Maps; Mass Spectrum Analysis; Measurement; Metabolic Pathway; Metabolism; method development; Methods; Metric; mevalonate; Modeling; Mutant Strains Mice; novel; Online Systems; Pathology; Pathway interactions; Phase; Plasma; programs; reconstruction; Regulation; Research; Research Infrastructure; research study; Resources; Statistical Data Interpretation; Statistical Methods; statistics; Structure; Systems Biology; Testing; Tissues; tool; Work
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5U54GM069338-09_9002 (2011): $470071
MICRORNA IN FUNCTIONAL REGULATION OF ENDOTHELIAL CELLS IN RESPONSE TO FLOW
Subramaniam Shankar
University Of California San Diegocity: La Jolla country: United States (us)
Grant 5R01HL106579-02 from National Heart, Lung, And Blood Institute
Keywords: Animals; Antiatherogenic; aortic arch; Apolipoprotein E; Apoptosis; Area; Arterial Fatty Streak; base; Bioinformatics; Biological; Biological Availability; Biology; Biomechanics; Blood flow; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; cDNA Arrays; Cell Line; Cell physiology; Complex; Computer Simulation; crosslink; Data; Data Analyses; Development; Diagnosis; Endothelial Cells; Endothelium; Event; functional genomics; Functional RNA; Gene Expression; Gene Expression Profile; gene function; Genes; genome-wide; Genomics; Histocompatibility Testing; Human Genome; Immunoprecipitation; In Vitro; in vivo; Inflammation; Inflammatory; innovation; insight; Lesion; Leukocyte Chemotaxis; Liquid substance; Literature; loss of function; Maintenance; Maps; Mechanics; Messenger RNA; MicroRNAs; Modeling; Modification; Molecular; Molecular Profiling; mouse model; mRNA Stability; multidisciplinary; Mus; novel strategies; Pathway interactions; Pattern; Phenotype; Play; protein expression; Proteins; Regulation; Research; Research Project Grants; research study; response; Role; shear stress; System; Systems Biology; Technology; Testing; Thoracic aorta; Tissue-Specific Gene Expression; Translational Repression; Trees; Vascular Endothelial Cell; Work
Relevance: MicroRNAs (miRs) are small non-coding RNAs that play crucial roles in the regulation of mRNA stability and translational repression, leading to the modulation of ~30% of the human genome. We will use in vitro, in vivo, and in silico technologies to develop an integrated systems approach to elucidate the roles of miRs in regulating endothelial functions in normal and pathophysiological flow conditions. The result may and may contribute to the development of novel approaches for the diagnosis and treatment of cardiovascular diseases
Project start date: 2011-01-01
Project end date: 2014-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01HL106579-02 (2012): $729180