Erzsébet Ravasz Regan, Ph.D.
Instructor of Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-270H
Boston, MA 02215
Erzsébet Ravasz Regan earned a Ph.D in Physics from the University of Notre Dame, Notre Dame, IN in 2004. She then started a two-year research fellowship at the Los Alamos National Laboratory as a Director Funded Postdoctoral Fellow. In late 2006 Dr. Ravasz Regan joined the Division of Molecular and Vascular Medicine at Beth Israel Deaconess Medical Center as a postdoctoral fellow, and became a member of CVBR as an Instructor in 2007.
Research Interests: Modularity of cellular regulation & endothelial heterogeneity
Basic Research - My group is interested in investigating biological systems from a complex networks perspective, with special emphasis on modularity of cellular dynamics, and the way modular regulatory systems handle the coordination of multiple phenotypic decisions. Most of our current topics are motivated by endothelial cell biology with emphasis on endothelial heterogeneity, and consist of computational work in collaboration with experimental laboratories at CVBR.
Organizing principles of dynamical modularity in biological regulation. Endothelial cells display extraordinary functional heterogeneity across the vasculature, a result of context-dependent coordination of a sizable functional arsenal. Deciphering how this coordination occurs remains problematic, in spite of detailed knowledge about individual functions. The central questions driving our research revolve around this problem. Are there general principles that govern coordination between regulatory modules? Can we use such principles to build a theoretical foundation for modeling multi-module regulatory systems? Is there a critical type of modularity that is key to deciphering a cell's higher-level responses? We have recently defined dynamical modules as robust, multistable regulatory switches and proposed three general principles that characterize coordination between these regulatory modules.
Biological noise-driven dynamic mosaic heterogeneity and functional bet hedging in vivo. We have found a novel adaptive strategy used by endothelial cells to increase their phenotypic plasticity and protect tissues from sudden environmental change. Briefly, the endothelium of healthy organs can exploit biological noise to generate a spatially heterogeneous, slowly flickering mosaic of Willebrand factor (vWF)-positive and -negative cells. These dynamic mosaics only appear in specific organs and vascular beds, such as heart capillaries. Their absence damages heart capillary endothelial cells and neighboring cardiomyocytes, but does not affect other vessels. Our data point to a novel, tissue-specific strategy for homeostasis.
Role of the Akt -| FoxO1 -> Akt negative feedback in endothelial life and death. The FoxO1 transcription factor affects multiple cellular functions such as cell cycle, apoptosis, ROS response, DNA repair, metabolism, aging ana differentiation. FoxO1 has been implicated in cancer, diabetes and muscle atrophy, but its effects are cell-type specific and often paradoxical. FoxO1 promotes cell cycle arrest and/or apoptosis in many cell types, but it's presence in the endothelium is required for embryonic vascular development. We have recently shown that endothelial FoxO1 is both necessary and sufficient for embryonic development. FoxO1 feeds back to up-regulate the activity of AKT and mTORC1, and its endothelial loss causes G1 arrest. Conversely, overexpression of FoxO1 induces both AKT and mTORC1 and promotes mTORC1-mediated cell growth. Excess FoxO1 nonetheless fails to increase proliferation, as it also induces G2 arrest. In contract, the FoxO1-AKT feedback does not induce mTORC1 in nonvascular cells. Pharmacological elevation of FoxO1 may thus promote quiescence and ROS resistance in some tissues, but carries the risk of damaging the vasculature.
New and Noteworthy Publications:
Bentley K, Philippides A, Ravasz Regan E. Do Endothelial Cells Dream of Eclectic Shape? Developmental Cell 2014; 29:146-158. This review/perspective explores the parallels between endothelial morphogenesis and the core principles of adaptive systems robotics. It introduces embodiment as critical for modeling cell shape change, the importance of sensors, controllers, and especially the effectors of motion, and discusses emergent behaviors of autonomous individuals (cells or robots) and their collectives.
Dharaneeswaran, H. Abid R, Yuan L, Dupuis D, Beeler D, Spokes KC, Janes L, Sciuto T, Kang P, Jaminet SC, Dvorak A, Grant MA, Ravasz Regan E, Aird WC, FoxO1-mediated Activation of Akt plays a critical role in vascular homeostasis. Circulation Research (in press), 2014. This study shows that endothelial FoxO1 is both necessary and sufficient for embryonic development, and that FoxO1 feeds back to upregulate the activity of Akt and mTORC1. Thus, in endothelial cells loss of FoxO1 causes G1 arrest, while its overexpression induces AKT and mTORC1, promoting cell growth but also G2 arrest.
Ravasz Regan E*, Aird WC. Dynamical systems approach to endothelial heterogeneity. Circulation Research 2012; 111:110-30 (*corresponding author). This perspective/review translates the basic tenets of dynamical systems theory into the language of endothelial biomedicine. It exposed the limitations of standard assumptions used to frame EC heterogeneity (e.g., natu re/nurture), and outlines the benefits of understanding cellular phenotypes as valleys on the energy landscape of regulatory circuits.
Ravasz E, Somera AL, Mongru DA, Oltvai ZN, Barabási AL. Hierarchical organization of modu- larity in metabolic networks. Science 2002; 297:1551. This highly cited study show that the metabolic networks of 43 distinct organisms are organized into many small, highly connected structural modules that combine in a hierarchical manner into larger, less cohesive units, with their number and degree of clustering following a power law. This hierarchical modularity closely overlaps with known metabolic functions in E. Coli.
Néda Z, Ravasz E, Vicsek T, Brechet Y, Barabási AL. The sound of many hands clapping, Nature 2000; 403:850.This study describes the repeated emergence and disappearance of synchronized clapping following theatrical performances as competition between synchronization and noise intensity, conflicting means of expressing appreciation for a performance.