how to mend a broken heart…...congenital heart defects are the most common congenital anomaly...
TRANSCRIPT
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How to mend a broken heart…
Ron Summers Professor of Information Engineering
Loughborough University
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Content
• Acknowledgements
• Genesis of Multiscale Engineering Concept
• Physiological Context
• Normal Heart Development
• Development in Congenital Heart Disease
• Modelling and Simulation
• Possible Future Scenarios
• Identifying the Engineering Components
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1. Acknowledgements
• Dr Hiten Vyas
• Prof Jean-Marc Schleich (Rennes)
• Dr Jean-Louis Dillenseger (Rennes)
• Dr Lucile Houyel (Paris)
• Dr Fanny Bajolle (Paris)
• Dr Tariq Abdulla (Warwick)
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Genomics
Sequencing,
Gene mining
& discovery
Gene
Expression
Microarray
experiments
Proteomics
Protein
Expression,
Structure,
Function,
Interactions
Systems
Biology
Regulation,
Metabolic
Pathways,
Protein
Pathways,
Cellular
Processes
(Patho)-
Physiology
Organ
Systems,
Chemical
Pathology
Epidemiology
Disease
spread,
Resistance,
Disease
evolution
Databases (Distributed, Various Formats)
Computational Analysis Tools
Information-driven discovery
Bio-, Pharma- applications Tissue engineering Clinical Trials
Summers & Vyas, 2004
2. Genesis of Multiscale Engineering Concept
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2. Genesis of Multiscale Engineering Concept
Definition of multiscale modelling
“…multiscale modelling is the field of solving
physical problems which have important
features at multiple scales, particularly
multiple spatial and (or) temporal scales”.
Wikipedia, accessed 2010
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From Genome to Function Genes
Health Organism
Organ
Tissue
Cell
Molecule
The Physiome Project http://www.physiome.org
Structure to Function:
• Experiments, Databases
• Problem Formulation
• Engineering the Solutions
• Quantitative System Modelling
• Archiving & Dissemination
Bassingthwaighte, 2002
3. Physiological Context
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3. Physiological Context
Hunter, Robbins & Noble, 2002
The Physiome Project
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after Summers et al., 2011
3. Physiological Context
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Srivastava & Olson 2000
4. Normal Heart Development
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4. Normal Heart Development
Abdulla et al., 2011
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Epithelial to Mesenchymal Transition
Notch Delta
4. Normal Heart Development
Abdulla et al., 2010
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4. Normal Heart Development
Protein Level
Abdulla et al., 2011
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4. Normal Heart Development
Anatomical
Perspective
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4. Normal Heart Development
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5. Development in Congenital Heart Disease
• Why is it important to better understand congenital heart
defects ?
• What is the Tetralogy of Fallot from an anatomical
standpoint ?
• Which embryological processes are involved in the
formation of the Tetralogy of Fallot ?
Clinical drivers for an engineering intervention:
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Why is it important to know more about congenital heart defects and
particularly about the Tetralogy of Fallot ?
Congenital heart defects are the most common
congenital anomaly observed in newborns – about
5-10 per 1000 births
10% of childhood mortality
Tetralogy of Fallot is the most common form of
cyanotic congenital heart disease. It affects 9%-
15% of all infants with congenital heart disease…
…and represents 55-70% of cyanotic congenital
malformations
We need to improve our knowledge about this
abnormality
5. Development in Congenital Heart Disease
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Tetralogy of Fallot
Pulmonary Stenosis
Ventricular Septal Defect by
malalignment
Dextroposition of the Aorta
(aortic overriding)
Right ventricular hypertrophy
5. Development in Congenital Heart Disease
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Anatomy of the Tetralogy of Fallot
Inter-ventricular septal defect Pulmonary stenosis
LV
RV
5. Development in Congenital Heart Disease
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5. Development in Congenital Heart Disease
Tetralogy of Fallot Normal Heart
* *
* Conal septum deviated anteriorly * Conal septum in normal position
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Which embryological processes are involved in the Tetralogy of Fallot ? Scale of tissue and cells
5. Development in Congenital Heart Disease
Bajolle, Zaffran & Bonnet., 2009
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Which embryological processes are involved in the Tetralogy of Fallot ? Scale of genetic signalling
5. Development in Congenital Heart Disease
Olson, 2006
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Wildtype Notch1 BMP2
in vitro Epithelial to Mesenchymal Transition
6. Modelling & Simulation
Luna-Zurita et al., 2010
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6. Modelling & Simulation
Wildtype
Abdulla et al., 2011
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6. Modelling & Simulation
Notch1
Abdulla et al., 2011
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6. Modelling & Simulation
BMP2
Abdulla et al., 2011
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7. Possible Future Scenarios
Summers et al., 2011 Scale Linking
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7. Possible Future Scenarios
Anatomic Re-determination of Tetralogy of Fallot
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8. Identifying the Engineering Components
• Systems Engineering Contribution • Multiscale Framework
• Methodology
• Cybernetics
• Modelling & Simulation • Cellular Potts models
• in vivo & in vitro samples • Microscopy
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after McCain & Parker, 2011
Intracellular Load
Extracellular Load
Cadherins
Titin
Integrins Cytoskeletal
Architecture
- Signalling
- Excitability
- Impulse propagation
- Contractility
- Gene expression Cytoskeletal
Remodeling Adaptative or
maladaptative growth
Intercellular Load
Direct or indirect activation of stretch activated channels
Mechanotransduction in the cardiovascular system
Functional
Response
8. Identifying the Engineering Components
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8. Identifying the Engineering Components
Olympus Fluoview FV-1000 Laser Scanning Confocal Microscope
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8. Identifying the Engineering Components
Liebling et al., 2006
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Thank You!
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References H. Vyas and R. Summers, ''Impact of Semantic Web on Bio-Informatics'', SSCC11, Amalfi, Italy, January 2004, ISBN 86 7466 117 3, [CD-ROM].
Shephard, 2006
Bassingthwaighte, 2002
P. J. Hunter, P. Robbins, and D. Noble, “The IUPS human Physiome Project.,” European Journal of Physiology, vol. 445, no. 1, pp. 1-9, Oct. 2002.
R. Summers, T. Abdulla, L. Houyel, and J. M. Schleich, “Progress with a Multiscale Systems Engineering Approach to Cardiac Development,”
Automatika, vol. 52, no. 1, pp. 49-57, 2011.
D. Srivastava and E. N. Olson, “A genetic blueprint for cardiac development.,” Nature, vol. 407, no. 6801, pp. 221-6, Sep. 2000.
T. Abdulla, R. A. Imms, J.-M Schleich, and R. Summers, “Towards Multiscale Systems Modeling of Endocardial to Mesenchymal Transition,” in
33rd Annual International Conference of the IEEE EMBS, 2011, pp. 449-452.
T. Abdulla, R. A. Imms, J.-M. Schleich, and R. Summers, “Systems modelling of EMT cell signalling pathways in heart valve development,” in VPH
2010, 2010.
F. Bajolle, S. Zaffran, and D. Bonnet, “Genetics and embryological mechanisms of congenital heart diseases.,” Archives of Cardiovascular
Diseases, vol. 102, no. 1, pp. 59-63, 2009.
E. N. Olson, “Gene regulatory networks in the evolution and development of the heart.,” Science, vol. 313, no. 5795, pp. 1922-7, 2006.
L. Luna-Zurita et al., “Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac
valve formation,” The Journal of Clinical Investigation, vol. 120, no. 10, pp. 3493-507, 2010.
T. Abdulla, J.-M Schleich, and R. Summers, “Multiscale Modelling of Notch-Mediated Lateral Induction,” in Proceedings of the IEEE-EMBS
International Conference on Biomedical and Health Informatics (BHI 2012), 2012, vol. 25, pp. 257-260.
M. L. McCain and K. K. Parker, “Mechanotransduction: the role of mechanical stress, myocyte shape, and cytoskeletal architecture on cardiac
function.,” European Journal of Physiology, vol. 462, no. 1, pp. 89-104, Jul. 2011.
M. Liebling et al., “Rapid three-dimensional imaging and analysis of the beating embryonic heart reveals functional changes during development.,”
Developmental Dynamics, vol. 235, no. 11, pp. 2940-8, Nov. 2006.