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SYSTEMS BIOLOGY APPROACH TO MODEL INFLAMMATION IN HUMAN CELLS

SYSTEMS BIOLOGY APPROACH TO MODEL INFLAMMATION IN HUMAN CELLS. BY, ROSHNI KISHOR BHATT M.S C –BIOTECHNOLOGY ,SEM-3 UKA TARSADIYA UNIVERSITY, BARDOLI. GUIDED BY, Mr , bhrugesh .p. joshi. INTRODUCTION. SYSTEMS BIOLOGY INFLAMMATION INSULIN APPLICATION OF SYSTEMS BIOLOGY REFERENCES .

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SYSTEMS BIOLOGY APPROACH TO MODEL INFLAMMATION IN HUMAN CELLS

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  1. SYSTEMS BIOLOGY APPROACH TO MODEL INFLAMMATION IN HUMAN CELLS BY, ROSHNI KISHOR BHATT M.SC–BIOTECHNOLOGY ,SEM-3 UKA TARSADIYA UNIVERSITY, BARDOLI. GUIDED BY, Mr, bhrugesh .p. joshi

  2. INTRODUCTION • SYSTEMS BIOLOGY • INFLAMMATION • INSULIN • APPLICATION OF SYSTEMS BIOLOGY • REFERENCES.

  3. SYSTEMS BIOLOGY • Systems biology studies biological systems by systematically perturbing them (biologically, genetically, or chemically); monitoring the gene, protein, and informational pathway responses; integrating these data; and ultimately, formulating mathematical models that describe the structure of the system and its response to individual perturbations.

  4. INTRODUCTION • Biological systems are enormously complex, organised across several levels of hierarchy. At the core of this organisation is the genome that contains information in a digital form to make thousands of different molecules and drive various biological processes. This genomic view of biology has been primarily ushered in by the human genome project. • The development of sequencing and other high-throughput technologies that generate vast amounts of biological data has fuelled the development of newways of hypothesis-driven research.Development of computational techniques for analysis of the large data, aswell as for the modelling and simulation of the complex biological systems have followed as a logical consequence. Simulatable computational models of biological systems and processes formthe cornerstone of the emerging science of systems biology.

  5. ELEMENTS OF SYSTEMS BIOLOGY

  6. Glossary of Some Terms Used and their Related Concepts • Genomics and other ‘omics’: • Genome Sequence • Gene Expression • Genotype and Phenotype • Network • Hub • Data-driven Modelling

  7. MODELING IN SYSTEMS BIOLOGY : MODEL ABSTRACTION

  8. KEY PROPERTIES OF BIOLOGICAL SYSTEMS/MODEL • Irreducibility. • Emergence. • Complexity. • Modularity. • Robustness and Fragility.

  9. PRACTIce OF SYSTEMS BIOLOGY • Models for Simulation • Biomodels.net http://www.biomodels.org/ • CellML http://www.cellml.org/ • Panther http://www.pantherdb.org/ • Pathway Databases • BioCyc http://biocyc.org/ • BioChemWeb http://www.biochemweb.org/ • KEGG Pathway http://www.genome.jp/ • Reactome http://www.reactome.org/

  10. Quantitative Data • BioPAX http://www.biopax.org/ • BRENDA http://www.brenda-enzymes.info/ • Systems Biology Standards • LibSBML (API) http://sbml.org/ • MathML http://sbml.org/ • SBML http://sbml.org/ • little b http://www.littleb.org/ • MIRIAM http://www.biomodels.org/

  11. Pathway Design and Network Based Tools • Cell Designer http://www.celldesigner.org/ • Cytoscape http://cytoscape.org/ • Jdesigner http://www.sys-bio.org/software/jdesigner.htm • Metatool http://www.biocyc.org/ • SBGN http://www.sbgn.org/Main_Page • Teranode http://www.teranode.com/

  12. GUI-Modelling and Simulation Tools • E-Cell http://www.e-cell.org/ • Gepasi http://www.gepasi.org/ • MATLAB http://www.mathworks.com/ • Maple http://www.maplesoft.com/ • SBML Toolbox http://sbml.org/ • Systems Biology Workbench (SBW) http://sbml.org/ • Non-GUI Modelling and Simulation Tools • Pathway Analyzer http://sourceforge.net/projects/pathwayanalyser • COBRA http://gcrg.ucsd.edu/ • JigCell http://jigcell.biol.vt.edu/

  13. INFLAMMATION • ACUTE INFLAMMATION

  14. The Inflammatory Cascade • Early Cell Responses: Ion exchange • Pseudopod formation by actin polymerization/depolymerization • Degranulation • Production and release of inflammatory mediators • Enhancement of endothelial permeability • Upregulation of membrane adhesion molecules • Tissue Degradation: Neutrophilentrapment in microvessels, transvascular migration • Platelet attachment, aggregation, thrombosis, red cell aggregation • Protease release and activation • Oxygen free radical formation • Apoptosis • Organ dysfunction.

  15. Initial Repair: Downregulation of anti-inflammatory genes • Upregulation of pro-inflammatory genes (cytokines, etc.) • Monocyte and T-Lymphocyte infiltration • Repair: Release of growth factors • Connective tissue growth • Revascularization • “Resolution of Inflammation”.

  16. THE EGFR: A SIGNALING HUB FOR INFLAMMATORY PATHWAYS • The expression of EGFR ligands is known to be increased during injury and inflammation in different organs and tissues. Perhaps one of the best studied cases is the inflammatory reaction of the skin, where the expression of ligandssuch as TGF-a and HB-EGF is markedly increased during wound healing and the targeted disruption of the EGFR has been shown to impair re-epithelializationafter injury. An interesting interaction between the EGFR system and innate immunity in epithelial cells is currently being elucidated. In this context, signaling through the EGFR seems essential to induce the expression of TLRs, such as TLR5 and 9, and it synergizes with these receptors to upregulate the production of inflammatory cytokines like IL-8 and antimicrobial peptides. The expression of AR and TGF-a is also known to be induced in chronic skin lesions such as psoriasis, where they are thought to promote IL-8 expression. Interestingly, IL-8 is in turn able to stimulate EGFR signaling through the metalloproteasemediated release of EGFR ligands, leading to a selfperpetuating Loop.

  17. INFLAMMATION MEDIATED BY CHEMOKINE AND CYTOKINE SIGNALING PATHWAY • Upon binding to a family of G-protein coupled seven-transmembrane receptors, chemokines (chemotactic cytokines) control and direct trafficking and migration of immune cells. This pathway illustrates chemokine-induced adhesion and migration of leukocytes resuling in the infiltration to the tissue and transcriptional activation enablingrecruitment of more leukocytes. Thus inhibiting specific chemokines and receptors could prevent the excessive recruitment of leukocytes to sites of inflammation.

  18. INSULIN • Insulin is the major hormone controlling critical energy functions such as glucose and lipid metabolism. Insulin activates the insulin receptor tyrosine kinase (IR), which phosphorylates and recruits different substrate adaptors such as the IRS family of proteins. Tyrosine phosphorylated IRS then displays binding sites for numerous signaling partners. Among them, PI3K has a major role in insulin function, mainly via the activation of the Akt/PKB and the PKCΖ cascades. Activated Akt induces glycogen synthesis, through inhibition of GSK-3; protein synthesis via mTOR and downstream elements; and cell survival, through inhibition of several pro-apoptotic agents (Bad, Forkhead family transcription factors, GSK-3). Insulin stimulates glucose uptake in muscle and adipocytes via translocation of GLUT4 vesicles to the plasma membrane. GLUT4 translocation involves the PI3K/Akt pathway and IR mediated phosphorylation of CAP, and formation of the CAP:Cbl:CrkII complex. Insulin signaling also has growth and mitogenic effects, which are mostly mediated by the Akt cascade as well as by activation of the Ras/MAPK pathway. A negative feedback signal emanating from Akt/PKB, PKCΖ, p70 S6K and the MAPK cascades results in serine phosphorylation and inactivation of IRS signaling.

  19. INSULIN SIGNALING PATHWAY.

  20. REFERENCES • 2009, Experimental Biology and Medicine. • Inhibition of signal transduction pathways involved in inflammation ,G. Haegeman • Computational systems biology: integration of sequence, structure, network, and dynamics Yong Wang1, Xiang-Sun Zhang1, LuonanChen2,3*From The 4th International Conference on Computational Systems Biology (ISB 2010) Suzhou, P. R. China. 9-11 September 2010. • Inflammatory pathways and insulin action GS Hotamisligil1*1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA • Pathway databases and tools for their exploitation: benefits, current limitations and challenges Anna Bauer-Mehren, Laura I Furlong* and Ferran Sanz • A comprehensive pathway map of epidermal growth factor receptor signaling Kanae Oda1,2, Yukiko Matsuoka1,3, Akira Funahashi. • Circuit diagrams for biological networks Kurt W Kohn and Mirit I Aladjem Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, MD, USA.

  21. QUESTIONS??????????

  22. THANKS!!!!!!!!!!!!!!!!!!!!!

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