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Ranjan K. Dash , Ph.D.
Associate Professor
Phone: (414) 955-4497

Fax: 414-955-6568
Email: rdash@mcw.edu

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 areas: Computational Biology and Bioinformatics
  Molecular and Cellular Physiology

Research Interests:

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.


Recent Publications:



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