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 genotypephenotype 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 ofthe 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.
| Williams, Nakeya D; Mehlsen, Jesper; Tran, Hien T et al. (2018) An optimal control approach for blood pressure regulation during head-up tilt. Biol Cybern : |
| Olsen, Christian Haargaard; Ottesen, Johnny T; Smith, Ralph C et al. (2018) Parameter subset selection techniques for problems in mathematical biology. Biol Cybern : |
| Wright, Peter T; Bhogal, Navneet K; Diakonov, Ivan et al. (2018) Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in ?2AR-cAMP Responsiveness in Murine Hearts. Cell Rep 23:459-469 |
| Ciocanel, Maria-Veronica; Docken, Steffen S; Gasper, Rebecca E et al. (2018) Cardiovascular regulation in response to multiple hemorrhages: analysis and parameter estimation. Biol Cybern : |
| Qureshi, M Umar; Colebank, Mitchel J; Schreier, David A et al. (2018) Characteristic impedance: frequency or time domain approach? Physiol Meas 39:014004 |
| Herum, Kate M; Choppe, Jonas; Kumar, Aditya et al. (2017) Mechanical regulation of cardiac fibroblast profibrotic phenotypes. Mol Biol Cell 28:1871-1882 |
| McClymont, Darryl; Teh, Irvin; Carruth, Eric et al. (2017) Evaluation of non-Gaussian diffusion in cardiac MRI. Magn Reson Med 78:1174-1186 |
| Sturdy, Jacob; Ottesen, Johnny T; Olufsen, Mette S (2017) Modeling the differentiation of A- and C-type baroreceptor firing patterns. J Comput Neurosci 42:11-30 |
| Tran, Kenneth; Han, June-Chiew; Taberner, Andrew J et al. (2016) Myocardial energetics is not compromised during compensated hypertrophy in the Dahl salt-sensitive rat model of hypertension. Am J Physiol Heart Circ Physiol 311:H563-71 |
| Lee, Pilhwa; Wolgemuth, Charles W (2016) Physical Mechanisms of Cancer in the Transition to Metastasis. Biophys J 111:256-66 |
Showing the most recent 10 out of 116 publications
