Ranjan K. Dash , Ph.D.
Phone: (414) 955-4497
Lab Website: http://bbc.mcw.edu/Computation
M.S. Mathematics, Utkal University, Orissa, India, 1991
Ph.D. Biofluid Dynamics, Indian Institute of Technology, Delhi, India, 1998
Postdoc. Biofluid Dynamics, Texas A&M University, College Station, 2000
Postdoc. Computational Biology, University of Washington, Seattle, 2003
Postdoc. Computational Biology, Case Western Reserve University, Cleveland, 2006
Research in Dr. Dash's laboratory is broadly focused on the development and application of computational models and tools for predicting and analyzing the behavior of complex physiological systems ranging over multiple scales of organization from molecular level to the whole-organism level. The overall goal of his research program is to work towards a quantitative understanding of the functioning of the living systems under normal and pathological conditions (health and disease) and guiding engineering-based manipulations of the systems. Over the past several years, he has contributed significantly to the research in the computational modeling and analysis of complex metabolic systems, including cardiac and skeletal muscle cellular metabolism and energetics, integrating tissue/organ-specific information over multiple scales ranging from transporter/enzyme to mitochondrial to cellular to tissue/organ levels. He has also extensive background in large-scale parameter estimation and sensitivity analysis of the problems arising from the modeling of physiological/metabolic systems. In a nutshell, his research for the past several years can be broadly classified into the following topics:
- Mathematical modeling and computer simulations of complex physiological systems;
- Computational algorithms for data analysis and parameter estimation (optimization);
- Microcirculatory oxygen and carbon dioxide transport and exchange;
- Multi-scale modeling of coupled blood-tissue solute transport and cellular energy metabolism in cardiac and skeletal muscles;
- Analysis of large-scale biochemical systems: regulation of cellular energy metabolism and mitochondrial oxygen consumption in cardiac and skeletal muscles;
- Mitochondrial handling of cations (Ca2+, Na+, K+, H+, Mg2+) and ROS (O2., H2O2).
Project 1: Multi-Scale Computational Modeling of Cellular Metabolism and Energetics
The biochemical pathways and processes of substrate and energy metabolism in tissue/organ systems (e.g., heart, skeletal muscle, liver) are highly complex. Substrates (e.g., glucose, fatty acids, amino acids) from capillary blood upon entering tissue cells undergo thousands of simultaneous biochemical reactions involving hundreds of biochemical species ultimately transducing free energy via mitochondrial oxidative phosphorylation in the form of ATP for use in various cellular functions. A quantitative understanding of the regulation of such complex metabolic pathways and processes is critical for a mechanistic understanding of the genesis of several cardiovascular diseases, including hypertension, heart disease, and diabetes. This requires sophisticated mathematical modeling, computer simulations, and validation with in vivo experimental data. Our efforts in this regard have been focused on the development of computational models and tools for simulating and analyzing the transport and reaction processes of biochemical species at various levels of metabolic complexity. Specifically, we are developing physiochemically-based, multi-scale, computational models of solute transport and cellular energy metabolism in the heart, skeletal muscle, and liver to predict and analyze the integrated molecular, subcellular, cellular, and whole-organ responses to physiological stimuli such as ischemia (decreased blood flow), hypoxia (decreased oxygen supply), exercise (increased energy demand), and hyperglycemia (increased blood glucose level). These models are crucial in establishing relationships between energy demand, oxygen supply, substrate availability, and blood flow in tissue/organ systems. These models are also helpful in linking external respiration (at the whole-body level) to internal respiration (at the whole-cell and mitochondrial levels). Our goal is to gain a quantitative understanding of the mechanisms of metabolic regulation in vivo in the cells of the heart, skeletal muscle, and liver, including the control of mitochondrial oxygen consumption, cellular respiration, substrate and energy metabolism, and ATP homeostasis during ischemia, hypoxia, exercise, and hyperglycemia conditions as well as how metabolic remodeling occurs in various metabolic diseases (e.g., heart failure and diabetes).
Project 2: Roles of Cations and ROS in Regulation of Mitochondrial Function
Given the fundamental role of mitochondria in cellular energetics and oxidative stress, it is widely believed that dysfunction within these organelles is involved in many aspects of cardiovascular diseases, such as hypertension, heart disease, and diabetes. Yet, our understanding of the role of mitochondria on the disease processes remains limited. Our recent research efforts have been focused on understanding how functional defects in the kinetics of mitochondrial cation (Ca2+, Na+, Mg2+, K+, and H+) transport and buffering and mitochondrial generation and scavenging of ROS (O2. and H2O2) affect overall mitochondrial bioenergetics and function. Our approach is to develop and apply biophysically-based mathematical models in conjunction with experimental observations in purified respiring cardiac mitochondria to quantitatively understand the roles of cations and ROS in the regulation of mitochondrial bioenergetics and function in the normal working hearts as well as in hearts with ischemia-reperfusion (IR) injury. Combining computational modeling and experimental measurements of mitochondrial bioenergetics and function provides an iterative process to formulate and quantitatively test complex hypotheses related to the kinetics of mitochondrial respiratory and transport systems, oxygen consumption, ATP synthesis, NADH and FAD redox states, membrane potential, cation transport and buffering, ROS generation and scavenging, and dynamic regulation of mitochondrial and cellular function in the heart in health and disease. The studies can provide a novel and rational mechanistic approach for identification of new therapeutic targets and development of new therapies (e.g., cation channel blockers or openers) to alleviate mitochondrial dysfunction.
- Agarwal B, Camara AKS, Stowe DF, Bosnjak ZJ, and Dash RK. Enhanced charge-independent mitochondrial free Ca2+ and attenuated ADP-induced NADH oxidation by isoflurane: Implications for cardioprotection. Biochim Biophys Acta Bioenergetics 1817(3): 453-465, 2012.
- Pradhan RK, Qi F, Beard DA, and Dash RK. Characterization of Mg2+ inhibition of mitochon-drial Ca2+ uptake by a mechanistic model of mitochondrial Ca2+ uniporter. Biophys J 101(9): 2071-2081, 2011.
- Qi F, Pradhan RK, Dash RK, and Beard DA. Detailed kinetics and regulation of mammalian 2-oxoglutarate dehydrogenase. BMC Biochem 12:53, 2011.
- Vinnakota KC, Dash RK, and Beard DA. Stimulatory effects of calcium on respiration and NAD(P)H synthesis in intact rat heart mitochondria utilizing physiological substrates cannot explain respiratory control in vivo. J Biol Chem 286(35): 30816-30822, 2011.
- Bazil JN and Dash RK. A minimal model for the mitochondrial rapid mode of Ca2+ uptake mechanism. PLoS One 6(6):e21324, 2011.
- Pradhan RK, Qi F, Beard DA, and Dash RK. Characterization of membrane potential dependency of mitochondrial Ca2+ uptake by an improved biophysical model of mitochondrial Ca2+ uniporter. PLoS One 5(10):e13278, 2010.
- Chen X, Qi F, Dash RK, and Beard DA. Kinetics and regulation of mammalian NADH-ubiquinone oxidoreductase (Complex I). Biophys J 99(5): 1426-1436, 2010.
- Haumann J#, Dash RK#, Stowe DF, Boelens AD, Beard DA, and Camara AKS. Mitochondrial free [Ca2+] increases during ATP/ADP antiport and ADP phosphorylation: Exploration of mechanisms. Biophys J 99(4): 996-1006, 2010. [# Equal contributions]
- Pradhan RK, Beard DA, and Dash RK. A biophysically-based mathematical model for the kinetics of mitochondrial Na+-Ca2+ antiporter. Biophys J 98(2): 218-230, 2010.
- Xie D, Dash RK, and Beard DA. An improved algorithm and its parallel implementation for solving a general blood-tissue transport and metabolism model. J Comp Phys 228: 7850-7861, 2009.
- Dash RK, Qi F, and Beard DA. A biophysically-based mathematical model for the kinetics of mitochondrial calcium uniporter. Biophys J 96(4): 1318-1332, 2009.
- Li Y#, Dash RK#, Kim J, Saidel GM, and Cabrera ME. Role of NADH/NAD+ transport activity and glycogen store on skeletal muscle energy metabolism during exercise - In silico studies. Am J Physiol Cell Physiol 296(1): C25-46, 2009. [# Equal contributions]
- Dash RK, Li Y, Kim J, Beard DA, Saidel GM, and Cabrera ME. Metabolic dynamics in skeletal muscle during acute reduction in blood flow and oxygen supply to mitochondria – In silico studies using a multi-scale, top-down integrated model. PLoS One 3(9): e3168, 2008.
- Dash RK and Beard DA. Analysis of cardiac mitochondrial Na+/Ca2+ exchanger kinetics with a biophysical model of mitochondrial Ca2+ handling suggests a 3:1 stoichiometry. J Physiol 586(13): 3267-3285, 2008.
- Dash RK, Li Y, Kim J, Saidel GM, and Cabrera ME. Modeling cellular metabolism and energetics in skeletal muscle: large-scale parameter estimation and sensitivity analysis. IEEE Trans Biomed Eng 55(4): 1298-1318, 2008.