The Virtual Physiological Rat Project

Summary

Principal Investigator: Daniel A Beard
Abstract: DESCRIPTION (provided by applicant): Many diseases (including heart disease, diabetes, cancer, and neurological disorders such as Parkinson's disease) cannot be understood in terms of single-cause/single-effect relationships. This is because although there exist both a depth of knowledge of basic physiology and a host of physiological and genomic data from animal models of disease, we lack an understanding of how multiple genes and environmental factors interact to determine phenotype. We propose to revolutionize our understanding of complex phenotypes and diseases based on systematic multi-scale measurement, simulation, and analysis of physiological function in the rat. Specifically, we propose to initiate The Virtual Physiological Rat Project to develop computational tools to capture the underlying systems physiology as well as the pathophysiological perturbations associated with disease. These tools will be developed and validated based on experimental characterization of physiological function across a number of organ systems in rat strains engineered to show relevant disease phenotypes. Computer simulation will be used to integrate disparate data (genomic, anatomic, physiological, etc.) to explain and predict function, and to translate the findings from animal models to yield new information on specific interrelated complex diseases in humans, including hypertension, kidney disease, heart failure, and metabolic syndrome. The developed multi-scale physiological models will be linked to genotype- phenotype parametric maps to construct a Virtual Physiological Rat resource, which will be used to predict the influence of genetic variability and environmental factors on phenotypes and to predict phenotypes of new strains that will be experimentally derived and characterized. By systematically and iteratively using multi-scale computational models to analyze data, generate hypotheses, design experiments, and predict phenotypes in novel strains of rat, we will attain the capability to predict and understand the emergence of complex traits. In addition to the direct impact of the proposed scientific studies, the VPR Center will be a resource to the broader community by delivering unique software and associated data for cardiovascular systems research. In addition, we will develop courses, workshops, and related educational material, train and recruit scientists from underserved communities, and hold annual scientific meetings for affiliated and nonaffiliated investigators. RELEVANCE: Despite a depth of knowledge of basic cardiovascular physiology, we lack even a rudimentary understanding of how multiple genes and environmental factors interact to determine cardiovascular phenotype. This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship.
Funding Period: 2011-08-11 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc Physiologically based pharmacokinetic tissue compartment model selection in drug development and risk assessment
    Matthew D Thompson
    Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    J Pharm Sci 101:424-35. 2012
  2. pmc Progression of glomerular filtration rate reduction determined in conscious Dahl salt-sensitive hypertensive rats
    Allen W Cowley
    Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Hypertension 62:85-90. 2013
  3. pmc Effect of regulatory architecture on broad versus narrow sense heritability
    Yunpeng Wang
    Centre for Integrative Genetics CIGENE, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, As, Norway
    PLoS Comput Biol 9:e1003053. 2013
  4. pmc Analysis of the kinetics and bistability of ubiquinol:cytochrome c oxidoreductase
    Jason N Bazil
    Center for Computational Medicine, Department of Physiology, Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Biophys J 105:343-55. 2013
  5. ncbi Patient-specific modelling of head-up tilt
    Nakeya D Williams
    Department of Mathematics, North Carolina State University, Raleigh, NC 27695, USA
    Math Med Biol 31:365-92. 2014
  6. pmc A C library for retrieving specific reactions from the BioModels database
    M L Neal
    Department of Bioengineering, University of Washington, Seattle, WA 98195, USA and Department of Computer Science, Wofford College, Spartanburg, SC 29303, USA
    Bioinformatics 30:129-30. 2014
  7. pmc Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model
    Robert C Lyon
    Department of Medicine
    Hum Mol Genet 23:1134-50. 2014
  8. pmc Toward GPGPU accelerated human electromechanical cardiac simulations
    Guillermo Vigueras
    Department of Biomedical Engineering, King s College London, UK
    Int j numer method biomed eng 30:117-34. 2014
  9. pmc A biophysically based mathematical model for the catalytic mechanism of glutathione reductase
    Venkat R Pannala
    Biotechnology and Bioengineering Center and Department of Physiology and
    Free Radic Biol Med 65:1385-97. 2013
  10. pmc A mechanistic mathematical model for the catalytic action of glutathione peroxidase
    V R Pannala
    Biotechnology and Bioengineering Center and Department of Physiology, Milwaukee, US
    Free Radic Res 48:487-502. 2014

Detail Information

Publications37

  1. pmc Physiologically based pharmacokinetic tissue compartment model selection in drug development and risk assessment
    Matthew D Thompson
    Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    J Pharm Sci 101:424-35. 2012
    ....
  2. pmc Progression of glomerular filtration rate reduction determined in conscious Dahl salt-sensitive hypertensive rats
    Allen W Cowley
    Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Hypertension 62:85-90. 2013
    ....
  3. pmc Effect of regulatory architecture on broad versus narrow sense heritability
    Yunpeng Wang
    Centre for Integrative Genetics CIGENE, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, As, Norway
    PLoS Comput Biol 9:e1003053. 2013
    ..Our approach can be used to elucidate these relationships across a whole range of biological systems in a systematic fashion...
  4. pmc Analysis of the kinetics and bistability of ubiquinol:cytochrome c oxidoreductase
    Jason N Bazil
    Center for Computational Medicine, Department of Physiology, Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Biophys J 105:343-55. 2013
    ..Moreover, the model is able to reproduce the bistability phenomenon where at a given overall flux through the enzyme, different rates of superoxide production are attained when the enzyme is differentially reduced. ..
  5. ncbi Patient-specific modelling of head-up tilt
    Nakeya D Williams
    Department of Mathematics, North Carolina State University, Raleigh, NC 27695, USA
    Math Med Biol 31:365-92. 2014
    ..Moreover, the model estimates physiologically reasonable values for arterial and venous blood pressures, blood volumes and cardiac output for which data are not available. ..
  6. pmc A C library for retrieving specific reactions from the BioModels database
    M L Neal
    Department of Bioengineering, University of Washington, Seattle, WA 98195, USA and Department of Computer Science, Wofford College, Spartanburg, SC 29303, USA
    Bioinformatics 30:129-30. 2014
    ..Our goal is to provide a useful tool for quantitative modelers who seek to accelerate modeling efforts through the reuse of previously published representations of specific chemical reactions...
  7. pmc Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model
    Robert C Lyon
    Department of Medicine
    Hum Mol Genet 23:1134-50. 2014
    ..In summary, we provide evidence for a novel mouse model, which is reminiscent of the postnatal onset of ARVC while highlighting mechanisms underlying a biventricular form of human ARVC. ..
  8. pmc Toward GPGPU accelerated human electromechanical cardiac simulations
    Guillermo Vigueras
    Department of Biomedical Engineering, King s College London, UK
    Int j numer method biomed eng 30:117-34. 2014
    ..Using the same human geometry, the GPU implementation of mechanics residual/Jacobian computation provided speedups of up to 44 × compared with SC and 2.0 × compared with MC...
  9. pmc A biophysically based mathematical model for the catalytic mechanism of glutathione reductase
    Venkat R Pannala
    Biotechnology and Bioengineering Center and Department of Physiology and
    Free Radic Biol Med 65:1385-97. 2013
    ..The kinetic model of GR may serve as a key module for the development of integrated models for ROS-scavenging systems to understand protection of cells under normal and oxidative stress conditions...
  10. pmc A mechanistic mathematical model for the catalytic action of glutathione peroxidase
    V R Pannala
    Biotechnology and Bioengineering Center and Department of Physiology, Milwaukee, US
    Free Radic Res 48:487-502. 2014
    ..The model provides a key component for an integrated model of H₂O₂ balance under normal and oxidative stress conditions...
  11. pmc Structural identifiability of viscoelastic mechanical systems
    Adam Mahdi
    Department of Mathematics, North Carolina State University, Raleigh, North Carolina, United States of America
    PLoS ONE 9:e86411. 2014
    ..We illustrate how to use our results in a number of examples and point to some applications in cardiovascular modeling. ..
  12. pmc Diffusion coefficients of endogenous cytosolic proteins from rabbit skinned muscle fibers
    Brian E Carlson
    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
    Biophys J 106:780-92. 2014
    ..Channeling of metabolic intermediates via enzyme complexes may enhance production of adenosine triphosphate at rates beyond that possible with randomly and/or sparsely distributed enzymes, thereby matching supply with demand. ..
  13. pmc Computational analysis of Ca2+ dynamics in isolated cardiac mitochondria predicts two distinct modes of Ca2+ uptake
    Shivendra G Tewari
    Biotechnology and Bioengineering Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 6509, USA
    J Physiol 592:1917-30. 2014
    ..In particular, it suggests that the Class 1 Ca(2+) buffering capacity is auto-regulated by the rate at which Ca(2+) is taken up by mitochondria. ..
  14. pmc A three-dimensional finite element model of human atrial anatomy: new methods for cubic Hermite meshes with extraordinary vertices
    Matthew J Gonzales
    Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
    Med Image Anal 17:525-37. 2013
    ..These new methods will allow for more compact and efficient patient-specific models of human atrial and whole heart physiology...
  15. pmc Beta-adrenergic stimulation maintains cardiac function in Serca2 knockout mice
    Sander Land
    Biomedical Engineering Department, King s College London, United Kingdom
    Biophys J 104:1349-56. 2013
    ....
  16. pmc Bridging the genotype-phenotype gap: what does it take?
    Arne B Gjuvsland
    Centre for Integrative Genetics, Department of Mathematical and Technological Sciences, Norwegian University of Life Sciences, Norway
    J Physiol 591:2055-66. 2013
    ....
  17. pmc A parallel algorithm for reverse engineering of biological networks
    Jason N Bazil
    Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, USA
    Integr Biol (Camb) 3:1215-23. 2011
    ..Moreover, the candidate network topologies returned by the algorithm can be used to design future experiments aimed at gathering informative data capable of further resolving the true network topology...
  18. pmc Parameters in dynamic models of complex traits are containers of missing heritability
    Yunpeng Wang
    Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, As, Norway
    PLoS Comput Biol 8:e1002459. 2012
    ....
  19. pmc Myocardial twitch duration and the dependence of oxygen consumption on pressure-volume area: experiments and modelling
    J C Han
    Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
    J Physiol 590:4603-22. 2012
    ....
  20. pmc Mechanisms of pressure-diuresis and pressure-natriuresis in Dahl salt-resistant and Dahl salt-sensitive rats
    Daniel A Beard
    Center for Computational Medicine, Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
    BMC Physiol 12:6. 2012
    ....
  21. pmc A practical approach to parameter estimation applied to model predicting heart rate regulation
    Mette S Olufsen
    Department of Science, Systems, and Models, Roskilde University, Universitetsvej 1, 4000, Roskilde, Denmark
    J Math Biol 67:39-68. 2013
    ..In conclusion, to avoid lengthy computations, these three methods may be combined for efficient identification of parameter subsets...
  22. pmc Use of partition coefficients in flow-limited physiologically-based pharmacokinetic modeling
    Matthew D Thompson
    Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    J Pharmacokinet Pharmacodyn 39:313-27. 2012
    ....
  23. pmc Multiscale modeling and data integration in the virtual physiological rat project
    Daniel A Beard
    Biotechnology and Bioengineering Center and Center for Computational Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
    Ann Biomed Eng 40:2365-78. 2012
    ....
  24. pmc Relating components of pressure-volume area in Suga's formulation of cardiac energetics to components of the stress-time integral
    J C Han
    Auckland Bioengineering Institute, Auckland, New Zealand
    J Appl Physiol (1985) 113:988-95. 2012
    ..We apply our results by examining retrospectively the interpretations reached in three independent studies published in the literature...
  25. pmc Slow Calcium-Depolarization-Calcium waves may initiate fast local depolarization waves in ventricular tissue
    Aslak Tveito
    Center for Biomedical Computing, Simula Research Laboratory, Norway
    Prog Biophys Mol Biol 110:295-304. 2012
    ..1 mm/s, b) faster Calcium-Depolarization-Calcium (CDC) waves, traveling at about 1 mm/s, and c) CDC-waves that can set off fast depolarization-waves (50 cm/s) in tissue with varying gap-junction conductivity...
  26. pmc Comparison of the Gibbs and Suga formulations of cardiac energetics: the demise of "isoefficiency"
    J C Han
    Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
    J Appl Physiol (1985) 113:996-1003. 2012
    ..We demonstrate that compatibility between the two formulations is thwarted by the concept of isoefficiency, the thermodynamic basis of which we show to be untenable...
  27. pmc Modeling to link regional myocardial work, metabolism and blood flows
    James B Bassingthwaighte
    Department of Bioengineering, University of Washington, Box 35 5061, 1705 NE Pacific St, Seattle, WA 98195 5061, USA
    Ann Biomed Eng 40:2379-98. 2012
    ..The object of this review is to argue that uniformity of work does not occur, and is impossible in any case, and that further experimentation and analysis are necessary to test the hypothesis...
  28. pmc Interpreting genetic effects through models of cardiac electromechanics
    S A Niederer
    Department of Biomedical Engineering, King s College London, King s Health Partners, Saint Thomas Hospital, London, UK
    Am J Physiol Heart Circ Physiol 303:H1294-303. 2012
    ..Finally, the potential for using this approach for ultimately predicting phenotypes from genetic sequence information is discussed...
  29. pmc A biophysical model of the mitochondrial ATP-Mg/P(i) carrier
    Shivendra G Tewari
    Biotechnology and Bioengineering Center and Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
    Biophys J 103:1616-25. 2012
    ..Moreover, computer simulations demonstrate that extramatrix Ca(2+) modulates the turnover rate of the APC and not the binding affinity of ATP, as previously suggested...
  30. pmc Specification, construction, and exact reduction of state transition system models of biochemical processes
    Scott M Bugenhagen
    Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    J Chem Phys 137:154108. 2012
    ..The method allows for the reduction of the otherwise intractable example models to a manageable size...
  31. pmc Identification of the kinetic mechanism of succinyl-CoA synthetase
    Xin Li
    Biotechnology and Bioengineering Center and Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53216, USA
    Biosci Rep 33:145-63. 2013
    ..A thermodynamically constrained set of parameter values is identified for this candidate mechanism...
  32. pmc Arterial stiffening provides sufficient explanation for primary hypertension
    Klas H Pettersen
    Department of Mathematical and Technological Sciences, Norwegian University of Life Sciences, As, Norway
    PLoS Comput Biol 10:e1003634. 2014
    ..In contrast to widely held opinions, the results suggest that primary hypertension can be attributed to a mechanogenic etiology without challenging current conceptions of renal and sympathetic nervous system function. ..

Research Grants30

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  2. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
    ..5 million from NICHD). The Center includes an excess of 70 Penn faculty at 15 departments at the Schools of Medicine, Veterinary Medicine, Nursing, the Wistar Institute, and the College of Arts and Sciences. ..
  3. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  4. Model-based predictions of responses RTK Pathway therapies
    Joe W Gray; Fiscal Year: 2013
    ..abstract_text> ..
  5. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  6. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  7. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..