Dr. Emilia Entcheva’s Lab Unjoo Lee

About her  She is an associate Professor Director, Cardiac Cell Engineering LabCardiac Cell Engineering Lab

About her  She is interested in cardiac cell function by integrating experimental and theoretical components

About her  She uses in vitro primary cell culture system, combined with nano- and microfabricated scaffolds and state-of-the- art fast optical mapping techniques for imaging cardiac electromechanics and structure.  Her lab develops and validates image-processing algorithms and biophysically realistic computational models to interpret the experimental findings and to provide insight in cardiac cell and tissue function and pathologies.  The functional characterization of the engineered tissue constructs in her lab and the direct testing and validation of computational models of cardiac cell function make this work especially valuable in outlining basic cellular responses for tissue engineering and tissue repair efforts.  She aims to establish a comprehensive model for studies of electrically or mechanically-triggered arrhythmogenesis and ways to prevent, modulate or terminate the undesired electrical abnormalities in the heart.

About her lab  Key Research Areas: Optical mapping of excitation Signal and image processing Cardiac cell and tissue engineering Mechanisms of arrhythmias  Members 2 post-Docs 3 Ph.D. students 5 under students

About her projects  Excitable Hybrid Automata (NSF grant CCF )  Bioelectricity in Hybrid Microstructured Cardiac Tissue (NSF grant BES ) BESC BESC

About her projects  Excitable Hybrid Automata Systems biology  An important open problem in systems biology is finding appropriate computational models that scale well for both the simulation and formal analysis of biological processes.  Large and complex sets of nonlinear differential equations, describing in painful detail the underlying biological phenomena. This project seeks to develop a hybrid- automata (HA) approach to modeling and analyzing complex biological systems, in aprticular, excitable cell networks.

About her projects  Excitable Hybrid Automata Details of the Project  Reaction-diffusion PDE systems  Hodgkin-Huxley (HH) formalism describing ion channel gating and currents  Initial results indicate that HA models, combining discrete and continuous processes, are able to successfully capture the morphology of the excitation event (action potential) of different cell types, including cardiac cells.  They can also reproduce typical excitable cell characteristics, such as refractoriness (period of non- responsiveness to external stimulation) and restitution (adaptation to pacing rates).

About her projects  Excitable Hybrid Automata Details of the Project  Multicellular ensembles of HA elements are used to simulate excitation wave propagation, including complex spiral waves underlying pathological conditions in the heart.  The resulting simulation framework exhibits significantly improved computational efficiency, and opens the possibility to formal analysis based on HA theory.

About her projects  Bioelectricity in Hybrid Microstructured Cardiac Tissue Cardiomyocytes, the main working and bioelectricity- generating cells in the heart exist and function in a social context of mesenchymal cells (mainly fibroblasts). Only recently, we start to ascribe to these non-excitable cell partners roles far beyond “space fillers” and “passive followers”. Cell communication and cell signaling events between different cell types are being recognized as important modulators in excitability and the propagation of electrical waves, and particularly in pathophysiological conditions. The long-term research goal of the PI is to contribute to and update the field of bioelectricity, including its educational aspect, by cross-fertilization with non- traditional design tools - cell/tissue engineering techniques and novel imaging modalities.

About her projects  Bioelectricity in Hybrid Microstructured Cardiac Tissue In this study, the PI proposes to develop advanced engineering techniques for designing cardiac microstructured hybrid networks (consisting of spatially patterned cardiomyocytes, CM, and fibroblasts, FB) and for imaging their bioelectric response with very high spatio-temporal resolution. Two specific hypothesis-driven projects will be undertaken to demonstrate the utility of this engineered hybrid cell platform to cardiac disease. First, we will tackle a fundamental bioelectricity question about the interaction between excitable and non-excitable cells in the heart and the contribution of mechanically-elicited events in electrical wave propagation in a controlled setting, using microscale electromechanical mapping. Second, we will characterize autocrine/paracrine modulation of cardiac bioelectricity by a class of locally-released signaling molecules (typically under increased load) - natriuretic peptides, NP, and the role of this cell signaling in arrhythmia induction/prevention.

About her projects  Bioelectricity in Hybrid Microstructured Cardiac Tissue The microstructured hybrid cardiac model and the specialized imaging tools, developed here, are directly applicable for basic studies in a wide range of research endeavors towards improving human health: 1) heart regeneration efforts: understanding transplant integration, cell signaling between native myocardium and newly introduced cells (stem cells, skeletal muscle cells, transfected fibroblasts), guided cell differentiation via cell signaling; 2) models of heart disease, involving hybrid cellular settings: fibrosis, cardiac hibernation; cardiac hypertrophy and heart failure; and 3) controlled models of the normal heart – understanding how different cell types communicate in side-by-side experiment-computer model validation.

About her projects  Bioelectricity in Hybrid Microstructured Cardiac Tissue The intellectual merit of the proposed research lies in the development of unique experimental tools for the precise manipulation of proteins and living cells and for their functional characterization for the better understanding of basic biosystem responses during dynamic inter-cellular interactions. The educational aspect of this project involves the translation of research into an enticing learning experience by incorporation of the developed here novel experimental components in teaching modules for an undergraduate Bioelectricity class, alongside with traditionally taught concepts; participants in Women in Science and Engineering (WISE) and a team of the Senior Design class will take active role in this translation process through PI-coordinated efforts. The broader impact of the results of this project for the scientific community and the society will come with improving fundamental understanding of cardiac bioelectricity in a complex cellular context.