Dash, Ranjan K., Ph.D. Assistant Professor Specialization: Computational Bioengineering Computational Group CV, Publications Tel:  (414)-955-4497 Fax: (414)-955-6568 Email: rdash@mcw.edu

Education and Training

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 Interests:
Research in our laboratory is broadly focused on the development and application of computational models and tools for predicting and analyzing the behavior of complex physiological systems, over multiple scale of organiza-tion ranging from molecular (enzymes/transporters) level to the whole-organism level. The overall goal of our 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 sys-tems. In a nutshell, our 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 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. We are also 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), and exercise (increased energy demand). These models are crucial in establishing relationships between energy demand, oxygen supply, substrate availability, and blood flow. 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, and exercise.

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 scav-enging 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 re-spiring cardiac mitochondria to quantitatively understand the roles of cations and ROS in regulation of mitochon-drial bioenergetics and function in the normal working hearts as well as in hearts with ischemia-reperfusion 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 electron transport, oxygen consumption, ATP synthesis, NADH and FAD redox states, membrane potential, cation transport and buffering, ROS generation and scavenging, and dynamic regulation of mitochon-drial and cellular function in the heart in health and disease. The studies can provide a novel and rational mecha-nistic approach for identification of new therapeutic targets and development of new therapies (e.g., cation chan-nel blockers or openers) to alleviate mitochondrial dysfunction.

Group Members:

Recent Publications:

• Pradhan RK, Beard DA, and Dash RK. A biophysically-based mathematical model for the kinetics of mitochon-drial Na+-Ca2+ antiporter. Biophys J, 2009 (in press).
• Dash RK, Qi F, and Beard DA. A biophysically-based mathematical model for the kinetics of mitochondrial cal-cium 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)
• Beard DA, Wu F, Cabrera ME, and Dash RK. Modeling of cellular metabolism and microcirculatory transport. Microcirculation 15(8): 777-793, 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, 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, Li Y, Kim J, Saidel GM, and Cabrera ME. Modeling cellular metabolism and energetics in skeletal mus-cle: large-scale parameter estimation and sensitivity analysis. IEEE Trans Biomed Eng 55(4): 1298-1318, 2008.
• Dash RK, Somersalo E, Cabrera ME, and Calvetti D. An efficient deconvolution algorithm for estimating oxygen consumption during muscle activities. Comput Meth Prog Biomed 85(3): 247-256, 2007.
• Lai N, Camesasca M, Saidel GM, Dash RK, and Cabrera ME. Linking pulmonary oxygen uptake, muscle oxygen utilization and cellular metabolism during exercise. Ann Biomed Eng 35(6): 956-969, 2007.
• Lai N, Dash RK, Nasca MM, Saidel GM, and Cabrera ME. Relating pulmonary oxygen uptake to muscle oxygen consumption at exercise onset: in-vivo & in-silico studies. Eur J Appl Physiol 97: 380-394, 2006.
• Dash RK and Bassingthwaighte JB. Simultaneous blood-tissue exchange of oxygen, carbon dioxide, bicarbonate and hydrogen ion. Ann Biomed Eng 34(7): 1129-1148, 2006.
• Dash RK, Bell BM, Kushmerick MJ, and Vicini P. Estimating in vitro mitochondrial oxygen consumption during muscle contraction and recovery: a novel approach that accounts for diffusion. Ann Biomed Eng 33(3): 343-355, 2005.