The Virtual Physiological Rat Project
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
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Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Hypertension 62:85-90. 2013....
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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...
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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. ..
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Department of Mathematics, North Carolina State University, Raleigh, NC 27695, USA
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Department of Bioengineering, University of Washington, Seattle, WA 98195, USA and Department of Computer Science, Wofford College, Spartanburg, SC 29303, USA
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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. ..
- Toward GPGPU accelerated human electromechanical cardiac simulationsGuillermo Vigueras
Department of Biomedical Engineering, King s College London, UK
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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...
- A mechanistic mathematical model for the catalytic action of glutathione peroxidaseV 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...
- Structural identifiability of viscoelastic mechanical systemsAdam 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. ..
- Diffusion coefficients of endogenous cytosolic proteins from rabbit skinned muscle fibersBrian E Carlson
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
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- Computational analysis of Ca2+ dynamics in isolated cardiac mitochondria predicts two distinct modes of Ca2+ uptakeShivendra 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. ..
- A three-dimensional finite element model of human atrial anatomy: new methods for cubic Hermite meshes with extraordinary verticesMatthew 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...
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Biomedical Engineering Department, King s College London, United Kingdom
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Centre for Integrative Genetics, Department of Mathematical and Technological Sciences, Norwegian University of Life Sciences, Norway
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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...
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Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, As, Norway
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Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
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- Mechanisms of pressure-diuresis and pressure-natriuresis in Dahl salt-resistant and Dahl salt-sensitive ratsDaniel A Beard
Center for Computational Medicine, Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
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- A practical approach to parameter estimation applied to model predicting heart rate regulationMette S Olufsen
Department of Science, Systems, and Models, Roskilde University, Universitetsvej 1, 4000, Roskilde, Denmark
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Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Biotechnology and Bioengineering Center and Center for Computational Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
Ann Biomed Eng 40:2365-78. 2012....
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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...
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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...
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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...
- Modeling to link regional myocardial work, metabolism and blood flowsJames 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...
- Interpreting genetic effects through models of cardiac electromechanicsS 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...
- A biophysical model of the mitochondrial ATP-Mg/P(i) carrierShivendra 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...
- Specification, construction, and exact reduction of state transition system models of biochemical processesScott 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...
- Identification of the kinetic mechanism of succinyl-CoA synthetaseXin 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...
- Arterial stiffening provides sufficient explanation for primary hypertensionKlas 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. ..
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- UNMC EPPLEY CANCER CENTER SUPPORT GRANTKenneth H Cowan; Fiscal Year: 2013....
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- Rocky Mountain Regional Center of Excellence or Biodefense and Emerging InfectiouJohn T Belisle; Fiscal Year: 2013..abstract_text> ..