Ranjan K. Dash, PhD
Physiology, Biotechnology & Bioengineering
Computational Biology and Bioinformatics/ Molecular and Cellular Physiology/ Metabolism 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 organization 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 systems. 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 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 regulation of mitochondrial 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 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.
Selected Recent Publications
Dash RK, Qi F, and Beard DA. A biophysically-based mathematical model for the kinetics of mitochondrial calcium uniporter. Biophys J, 2009, 96(4):1318-1332.
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 2009, 296(1):C25-46.
Beard DA, Wu F, Cabrera ME, and Dash RK. Modeling of cellular metabolism and microcirculatory transport. Microcirculation 2008, 15(8):777-793.
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 2008, 586(13):3267-3285.
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 2008, 3(9): e3168.
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 2008, 55(4):1298-1318.