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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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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


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

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 sheart 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 modelsfunctional genomics

  • large animal models physiology

  • humanclinical MRI, CT, etc


The iups physiome project auckland bioengineering institute maurice wilkins centre

Heart Physiome

Cardiac Structure


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

Karl Tomlinson

Activation sequence

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

Electro-mechanics in ventricular tissue

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

Nic Smith

Coronary flow & energetics

Smith NP, Pullan AJ & Hunter PJ. SIAM J Appl Maths 62:990-1018, 2002


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

Lung physiome

Auckland, Iowa & Oxford

blood vessels

airways

alveoli

diaphragm

gas exchange

Eric HoffmanU Iowa

Merryn Tawhai


The iups physiome project auckland bioengineering institute maurice wilkins centre

Musculo-skeletal physiome

Kumar Mithraratne

JustinFernandez


The iups physiome project auckland bioengineering institute maurice wilkins centre

Andrew Pullan

Martin Buist

Digestive system physiome

Auckland, Singapore, Nevada & Vanderbilt


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

FieldML & Cmgui


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


The iups physiome project auckland bioengineering institute maurice wilkins centre

Model repository (www.cellml.org/models)


The iups physiome project auckland bioengineering institute maurice wilkins centre

CellML Tools (www.cellml.org/tools)

(a) Model components & metadata

(b) MathML editor

Cmgui

(c) Graphical display

(d) Simulation software


The iups physiome project auckland bioengineering institute maurice wilkins centre

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


Acknowledgements

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 projectEU 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

& …


The iups physiome project auckland bioengineering institute maurice wilkins centre

Our graduate students

& postdocs


The iups physiome project auckland bioengineering institute maurice wilkins centre

www.physiomeproject.org

www.cellml.org

www.bioeng.auckland.ac.nz


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