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Curate Hepatology Models: An Update

Curate Hepatology Models: An Update. Harvey Ho, Hanne Nielsen, Peter Hunter Bioengineering Institute University of Auckland, New Zealand CellML Workshop, Auckland, New Zealand 13 March 2012. Background Why systems biology? International Initiatives Hepatology Model Curation

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Curate Hepatology Models: An Update

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  1. Curate Hepatology Models: An Update Harvey Ho, Hanne Nielsen, Peter Hunter Bioengineering Institute University of Auckland, New Zealand CellML Workshop, Auckland, New Zealand 13 March 2012

  2. Background • Why systems biology? • International Initiatives • Hepatology Model Curation • Previous work • Models added • Issues arising • Future Direction - Some personal thoughts • Create cutting-edge models • Clinical connection Outline 2

  3. Section I: Background

  4. Why systems biology? Background Image source: SBMC’2012 “The rhythmicity of the heart is not encoded at a subcellular level – so looking for a genetic basis for this behaviour, for example, is futile - but first emerges at the level of the individual cell. It is modulated as the other layers of the system are combined: from an individual cell, the electrophysiology of its encapsulating membrane, up to the tissue level and finally whole organ” - Denis Nobel

  5. Background Systems biology for the liver: • The same methodology applies to the liver • ‘Top-down’ and ‘Bottom-up’ *Abbott, Germans cook up live project, Nature, Vol 468, P879 *Abbott, Germans cook up live project, Nature, Vol 468, P879

  6. Int’l Research HepatoSys project • €36M project, 2004-2009 by the German Federal Ministry of Education and Research (BMBF) • Investigates all processes within the liver, with a focus on hepatocytes

  7. Int’l Research Virtual Liver Network • with funding €42M for 5 years • ~250 scientists in 69 research groups in Germany • Three major areas of focus: • The Liver Cell • Beyond the Cell • Integration and Translation *Abbott, Germans cook up live project, Nature, Vol 468, P879, 2010

  8. Section II: Curate Hepatology Models

  9. Previous work • Papers sourced from HepatoSys publication (Jan 2009) • Total papers: 249 • Keyword ‘Platform Modelling’: 58 • Selection criteria • Equation formation • Parameter completeness • Initial conditions

  10. Previous work amino acid metabolism Acikgoz 2009 Guthke 2006 Drug biotransformation liver regeneration Chauhan 2008 Klamt 2003

  11. Issues Arising • Uncodable Models • Missing Units and Initial Values - have to make guesses -> uncertainty • Errors in Printed Papers • Invalid emails for published author contacts 11

  12. Curate New Models Methods/Strategy • Smaller models first, then larger models • Older models first, then newer models • Connection between models • Model evolution • Collaborators, strategically important

  13. Examples Larsen_2003 • Models of Prof. Ursula Kummer (Dept of Modeling of Biological Processes, Uni of Heidelberg) Grubelnik _2001 Kummer_2000 Marhl_2000 1. Grubelnik et al, ‘Mitochondria regulate the amplitude of simple and complex calcium oscillations’, 2001 Biophysical Chemistry, 94, 59-74. 2. Kummer et al, ‘Switching from Simple to Complex Oscillations in Calcium Signaling’, 2000 Biophysical Journal, 79, 1188-1195

  14. Examples Gall_2009 • Model evolution diagram Gall_2000 Cardenas_1996 Dupont_1992 Goldbeter, Berridge 1. Gall et al, ‘Activation of the Liver Glycogen Phosphorylase by Ca2+ Oscillations: a Theoretical Study‘, 2000, Journal of Theoretical Biology, 207, 445-454 2. Cardenas and Goldbeter, ‘The Glucose-induced Switch Between Glycogen Phosphorylase and Glycogen Synthase in the Liver: Outlines of a Theoretical Approach’, 1996 Journal of Theoretical Biology, 182, 421-426.

  15. Other curated models Swat_2004 mammalian G1/S transition metabolism schmitmeier_2007

  16. Other curated models

  17. Section III: Future Direction Some Personal Thoughts 17

  18. CellML • What we have learned? • Model evolution • Hierarchy • Public, private interface • Understand the underlying physiology • Different components integrated to form a new model • Work with key research groups • User requirement • Proactive curating

  19. Collaboration with transplantation surgeon, interventional radiologists Clinical Connection • Liver resection to treat tumour • Liver transplantation Connect to microscale models Image courtesy of Dr. Adam Bartlett 19

  20. Dedicated to Prof. Andrew Pullan (1963-2012) Clinical connection “The other drug ipilmumab cannot be considered an option at this stage as my liver is too compromised to be able to handle it.”, 14 Jul 2011http://andrewsrecovery.blogspot.co.nz/ • Drug induced liver injury • Hepatotoxity • mitochondrial damage • reactive metabolite effects • … • Toxicity pathways -> safer drugs Circulation model Homeostasis of hepatocytes, inflammatory mediator secretion from Kupffer cells Gene signature for hepatotoxity

  21. Thanks for your attention. Questions? 21

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