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The IUPS Physiome Project Auckland Bioengineering Institute & Maurice Wilkins Centre

BMSW 2008, Bangalore, India. The IUPS Physiome Project Auckland Bioengineering Institute & Maurice Wilkins Centre University of Auckland, NZ. Genes. mRNA. Proteins Lipids Carbohydrates. Cell structure -function. Tissue structure -function. Organ structure -function. Clinical medicine.

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The IUPS Physiome Project Auckland Bioengineering Institute & Maurice Wilkins Centre

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  1. BMSW 2008, Bangalore, India The IUPS Physiome Project Auckland Bioengineering Institute& Maurice Wilkins Centre University of Auckland, NZ

  2. Genes mRNA Proteins Lipids Carbohydrates Cellstructure-function Tissuestructure-function Organstructure-function Clinical medicine … PhysiomeProject Genome/Transcriptome/Metabolome/Proteome 4 tissue types 25,000 genes 100,000+proteins 200+ cell types 12 organsystems 1 body 1. IUPS Physiome Project Hunter, PJ and Borg, TK. Integration from proteins to organs: The Physiome Project. Nature Reviews Molec & Cell Biol. 4:237-243, 2003

  3. Space 109 • 1 mperson • 1 mmelectrical length scale of cardiac tissue • 1 mmcardiac sarcomere spacing • 1 nmpore diameter in a membrane protein Time 1015 • 109 s (70 yrs)human lifetime • 106 s (10 days)protein turnover • 103 s (1 hour)digest food • 1 s heart beat • 1 msion channel HH gating • 1 msBrownian motion Requires a hierarchy of inter-related models gene reg. networks pathway models MD/CG models stochasticmodels PDEs (continuum models) ODEs The Challenge: spatial and temporal scales • The diversity of experimental models • bacterial modelsstructural biology • murine models functional genomics • large animal models physiology • human clinical MRI, CT, etc

  4. Heart Physiome Cardiac Structure

  5. Large deformation elasticity theory Finite element method Element with Hermite basis x3 u,u,u ,etc x1x2 x2 material coordinates x1 Element fields: undeformed coords X,Y,Z (or l,m,q) deformed coords x,y,z fibre & sheet orientations electrical potential concentration fields for Ca2+, O2 , etc Equations: Integral formulation - Galerkin method - Gaussian quad Costa KD, Hunter PJ, Wayne JS, Waldman LK, Guccione JM & McCulloch AD. ASME J. Biomech. Eng. 118:464-472, 1996 Nash MP and Hunter PJ. J. Elasticity. 61(1-3):113-141, 2001

  6. Transmural confocal image of rat myocardium Endo Axial tension fibre axis Epi sheet axis sheet normal Axial strain normal sheet fibre Constitutive Relations Pole-zero constitutive law: W = k11e112 + k22e222 + …. (a11-e11)2 (a22-e22)2 pole

  7. Myocardiac Activation Inward current pushes the voltage up V Action potential duration is critical time SCN5A + subunits Sodium current CACH1C L-type calcium current T-type calcium current NCX Na-Ca exchange Kv4.x ITO1 (4-AP-sensitive) ITO2 (Ca-activated) KvLQT1 + minK IKs Outward current IKr HERG + MiRP-1 Kv1.5 IKur or IKq ICl or IKp CFTR, TWIK Kir2.x IK1 (inward rectifier) Kir3.1/3.4, Kir6.x/SUR IK ATP/ACh If (pacemaker) hCNG Membrane ion channels Denis Noble Probable clones CellML

  8. Karl Tomlinson Activation sequence Tomlinson KA, Pullan AJ & Hunter PJ. SIAM J Applied Maths. 63(1):324–350, 2002

  9. Solve tissue mechanics for deformed mesh Update grid point extension ratios Solve cell eqtns for T, z … 1 2 3 Boundary forces X X X X Update T at Gauss pts 5 4 For time dep. cell model, iterate to convergence at each time step Cell to tissue coupling • Given: • initial geometry • boundary conditions Buist ML, Sands GB, Hunter PJ and Pullan AJ. Annals BME 31:577-588, 2003

  10. Electro-mechanics in ventricular tissue Nickerson, Smith & Hunter. New developments in a strongly coupled cardiac electromechanical model. Europace, 7, S118-S127, 2005

  11. Nic Smith Coronary flow & energetics Smith NP, Pullan AJ & Hunter PJ. SIAM J Appl Maths 62:990-1018, 2002

  12. Organ system Physiome Projects Cardiovascular system Respiratory system Musculo-skeletal system Digestive system Skin (integument) Urinary system Lymphoid system Female reproductive system Special sense organs Central nervous system Endocrine system Male reproductive system

  13. Lung physiome Auckland, Iowa & Oxford blood vessels airways alveoli diaphragm gas exchange Eric HoffmanU Iowa Merryn Tawhai

  14. Musculo-skeletal physiome Kumar Mithraratne JustinFernandez

  15. Andrew Pullan Martin Buist Digestive system physiome Auckland, Singapore, Nevada & Vanderbilt

  16. OMIN, Medline PubMed SNPbase, … Organism (7) Circulatory system Respiratory system Musculo-skeletal system Skin (integument) Digestive systemCentral nervous system Endocrine systemLymphoid systemMale reproductive system Female reproductive system Special sense organs OrganSystem(6) AnatML Organ (5) Muscle tissue Nerve tissue Connective tissue Epithelial tissue FieldML TissueML Structure CellML PIR SwissProt Prosite Genome Protein dbEST dSTS RNA GenBank EMBL, DDBJ TIGR DNA Tissue (4) Cell (3) PDB SCOPs Molecule (2) Atom (1) Physiome MLs, tools & databases

  17. Strategy: 1. Develop MLs for encoding models 2. Develop libraries of open source tools 3. Develop model repositories based on MLs 4. Implement collaborative project environments 5. Implement workflows based on web services

  18. FieldML & Cmgui

  19. CellML (www.cellml.org) PoulNielsen • CellML models include information about: • model structurehow the parts of a model are related to one another • mathematics(MathML)equations describing the underlying processes • metadata(RDF)additional information about the model that allows scientists to search for specific models or model components in a database or other repository

  20. Model repository (www.cellml.org/models)

  21. CellML Tools (www.cellml.org/tools) (a) Model components & metadata (b) MathML editor Cmgui (c) Graphical display (d) Simulation software

  22. Summary • The Physiome project is about: • Models that capture patient-specific geometry(link to clinical imaging) • Multi-physics models based on biophysical mechanisms(can use power of physical constraints) • Constitute laws based on tissue microstructure(only way to deal with spatial variation) • Multi-scale models that link to proteins(can link to disease & drug action) • We need: • Open source software • Markup language standards for encoding models • Web accessible model databases • HPC & grid-enabled tools for collaboration

  23. Acknowledgements: Funding: Heart Foundation of NZ Health Research Council of NZ Royal Society NZ Marsden Fund Fdn for Research, Science & Technology Maurice Wilkins Centre CoRE NIH, NSF Wellcome Trust, UK EPSRC eScience Integrative Biology project EU FP6 Colleagues in the Auckland Bioengineering Institute (ABI) & the Maurice Wilkins Centre (MWC) Colleagues in Oxford: Denis Noble, David Paterson, Peter Kohl & many other colleagues around the world & …

  24. Our graduate students & postdocs

  25. www.physiomeproject.org www.cellml.org www.bioeng.auckland.ac.nz

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