About the Lab
We are a biomedical engineering laboratory working to understand the structural underpinnings of electrical signal propagation in the heart, and how their disruption leads to potentially life-threatening arrhythmias (irregular heartbeats). It has become clear over recent years that the heart’s physiology at cellular and organ levels is governed by the behavior of handfuls of proteins organized into nano-machines – structures 10,000 times smaller than the width of human hair.
We are working to understand the protein composition and structural properties of different nano-machines within muscle cells of normal and diseased hearts. This will help us develop new types of treatments for heart disease, which will restore these nano-machines and thereby, the heart itself, to normal. Our approach to this research uses cutting-edge light and electron microscopy techniques to visualize the protein nano-machines, and computational image analysis techniques to precisely and reliably measure the difference between health and disease at the nano level.
In pursuing this scientific mission, we are often challenged by the limits of current microscopy and image analysis methods. Therefore, a substantial part of our efforts are aimed at inventing new techniques to overcome these limits.
Vascular leak and Atrial fibrillation (AF): Atrial fibrillation (AF) is the most common arrhythmia (irregular heartbeat), affecting up to 3% of the US population. AF patients experience abnormally high levels of fluid leak from their blood vessels (vascular leak), which can increase the risk of blood clots and stroke. In ongoing research, we are finding out that vascular leak may directly contribute to the development and progression of AF. Based on this, we are developing new treatments for AF.
Nanoscale basis of cardiac impulse propagation (Collaboration: Weinberg lab): Each heartbeat involves ~12 billion muscle cells contracting in a precise sequence. This is coordinated by electrical signals spreading from cell to cell. Recent research suggests that electrical signal propagation at cellular and tissue scales results from the behavior of nanodomains (structures 10,000 times smaller than the width of a human hair), each containing a handful of key ion channel proteins. We are using cutting-edge light and electron microscopy, along with computational image analysis, to find and characterize these structures. We are also uncovering the functional roles of different types of nanodomains by selectively manipulating their structures in experiments. These data are utilized by the Computational Physiology Lab, led by Dr. Seth Weinberg, to develop computational models of cardiac electrical signaling with unprecedented levels of structural detail. These models will help us understand underlying mechanisms and generate predictions for further experimental testing. Through these efforts, we hope to uncover structure-function relationships at the nanoscale, and lay the foundation for a new age of therapies for heart disease.
ID nanodomains and AF: This project provides a direct example of the application of our work on nanodomains involved in the spread of electrical signals through the heart. We previously found these nanodomains to be damaged in the hearts of AF patients. In ongoing work, we are finding that such nanodomain damage can occur dynamically (within minutes) in an otherwise healthy heart and acutely increase the risk of AF. We are also learning that the functional impact of nanodomain damage can be predicted based on their protein composition. This work could help us understand how AF develops at the very earliest stages of the disease, and importantly, to develop drugs that reverse the disease process by protecting key nanodomains.
Nanoscale basis of cardiac sodium-calcium cycling (Collaboration: Radwański lab): During each heartbeat, ~12 billion muscle cells must contract in response to electrical signals. These processes are bridged by the movement of sodium and calcium in and out of the cells. In disease states, abnormal movement of sodium and calcium lead to potentially life-threatening irregular heartbeats. Previous work from the Radwański and Györke labs has identified a small proportion of brain-type sodium channels in the heart, which exert a disproportionate level of control over sodium-calcium cycling in the heart. In ongoing work, we are learning that this effect results from these sodium channels being located just nanometers from calcium handling proteins, and developing ways to selectively target them with drugs to prevent irregular heartbeats.
Non-canonical mechanisms of cardiac calcium cycling (Collaboration: Györke lab): Beat-to-beat calcium movements in the heart are so large and rapid, that they were thought to render irrelevant the slower movement of calcium through a second process termed store-operated calcium entry (SOCE). Yet, defects in SOCE proteins have been linked to irregular heartbeats in human patients. Working with the Györke lab, we are learning that the protein machinery of SOCE exists within distinct structural compartments inside the heart muscle cell, located far enough away from the proteins involved in beat-to-beat calcium movement to play an important role in the heart’s physiology. We are continuing to uncover the roles of SOCE in the normal and the diseased hearts with the goal of developing ways to target SOCE to prevent the development of heart disease.
Cell Atlas: No cell is shaped like another. This complicates comparison of microscopy images showing different structural aspects (proteins, nucleic acids, protein-protein interactions). We are developing a cell atlas, a mathematical tool to consistently map structural features from any cell imaged on to an “average cell” by parameterizing the positions of structures in relation to the nucleus and cell periphery. Using this, results from separate experiments and even different imaging modalities can be combined into a single cohesive dataset.
Indirect Correlative Light and Electron Microscopy (iCLEM): Recently developed super-resolution light microscopy techniques can resolve structures as small as 10 nanometers. They bring the versatility of light microscopy (the ability to identify specific biomolecules) to scales historically only accessible to electron microscopy. Correlative light and electron microscopy (CLEM), which combines these approaches, promises even greater investigative power. Current CLEM methods are extremely expensive and difficult, and yield a small number of images with little to no quantitative measurements. We propose to solve this problem by developing iCLEM: a family of imaging and computational image analysis techniques, designed to yield robust, quantitative measurements of the nanoscale structure of cells and tissues at a fraction of the cost. iCLEM takes advantage of structural fiducials (landmarks identifiable by both light and electron microscopy) to correlate hundreds, even thousands of measurements made from separately collected light and electron microscopy images. iCLEM will simultaneously deliver major advances in experimental throughput (the number of measurements made) and repeatability by utilizing unbiased, automated computational image analysis tools to make these measurements.
Quantifying Spatial Protein Organization: Understanding how proteins are organized relative to each other is vital to understanding living systems. At present, this is assessed using co-localization analysis. This method is overly simplistic and limited, reducing the spatial organization of proteins to a single metric of signal superposition. It also cannot be used on single molecule localization data, a problem we previously solved by developing STORM-RLA, a machine learning-based cluster analysis approach. We are now developing methods to provide a rich, quantitative assessment of the protein spatial organization from both fluorescence images (using object-based segmentation) and single molecule localization data (a machine learning-based approach with radically improved precision and capabilities over STORM-RLA). These methods will work with a wide range of microscopy techniques, and provide quantitative results in a standardized data format.
“Equipped with our five senses, along with telescopes and microscopes and mass spectrometers and seismographs and magnetometers and particle accelerators and detectors across the electromagnetic spectrum, we explore the universe around us and call the adventure science.”
– Neil deGrasse Tyson paraphrasing Edwin Hubble
Science is the most robust method yet devised to satisfy our innate human need to explore and understand reality and tools, such as microscopes, extend our reach far beyond the limited grasp of our senses. As such, we view science as an everyday life skill and microscopes as everyday tools. Added to this, microscopes have the ability to provoke wonder in child and adult alike. And, last but not least, frugal microscopy technologies are available, which provide significant investigative power at low cost ($1-15 / unit). Thus, we believe that microscopes are an ideal tool for promoting exploratory learning of Science, Technology, Engineering, Arts, and Mathematics (STEAM) education starting at the K-12 level. To this end, we have established partnerships with K-12 educators in the central Ohio region, and fellow microscopists / educators from the Microscopy Society of America (MSA) to implement microscopy-based outreach activities (informal education) as a pathway to integrating microscopy-based exploration into the formal curriculum.
- Nov-2020: Sai Veeraraghavan participates in the Ask a Microscopist live webinar series organized by the MSA Student Council (including Secretary and Nanocardiology lab member, Louisa Mezache).
- Nov-2020: Heather Struckman and Sai Veeraraghavan demonstrate STORM single molecule localization microscopy as part of the Microscopy Live webinar series organized by the MSA Student Council
- Oct-2020: Sai Veeraraghavan (as chair of the MSA Education-Outreach Committee) co-organizes the first ever “Microscopy in the Classroom” virtual symposium featuring panelists and participants from around the world. Heather Struckman participates as a panelist.
- Feb-2020: Heather Struckman and Sai Veeraraghavan win separate Strategic Initiative awards from the Microscopy Society of America to pursue education-outreach. https://bme.osu.edu/news/2020/02/veeraraghavan-lab-awarded-microscopy-ou...
- Aug-2021: Heather Struckman (2 oral presentations) and Louisa Mezache (poster) selected to present abstracts at the 2021 American Heart Association Scientific Sessions.
- Aug-2021: Heather Struckman (oral presentation), Louisa Mezache (poster) and Andrew Soltisz (oral presentation) present 3 abstracts at the 2021 Microscopy & Microanalysis Annual Meeting. Andy Soltisz selected for a Student Scholar Award.
- Aug-2021: Heather Struckman's paper (Struckman et al., Microsc Microanal 2020) awarded best paper in the biological sciences in 2020 by the journal.
- July-2021: Louisa Mezache presents an abstract at the 2021 Heart Rhythm Society Annual Scientific Sessions.
- Jun-2021: Louisa Mezache selected to present an abstract at the 2021 AHA Basic Cardiovascular Sciences Conference.
- May-2021: Louisa Mezache and Heather Struckman selected to present abstracts at the 2021 Gordon Research Conference on Cardiac Arrhythmia Mechanisms.
- Mar-2021: Sai Veeraraghavan receives a Lumley Research Award from the OSU College of Engineering.
- Mar-2021: Heather Struckman selected for an oral presentation at the 2021 OSU Edward G. Hayes Graduate Research Forum.
- Feb-2021: Heather Struckman (oral presentation), Louisa Mezache (poster) and Andrew Soltisz (poster) present 3 abstracts at the 2021 Annual Meeting of the Biophysical Society. Our collaborations with the Gyorke and Weinberg labs resulted in a further 4 abstracts presented.
- Nov-2020: Mezache et al manuscript demonstrating novel mechanism for atrial fibrillation published in Scientific Reports.
- Nov-2020: Nanocardiology lab awarded AHA Transformative Project grant to develop new therapies for atrial fibrillation.
- Aug-2020: Louisa Mezache elected Secretary of the Microscopy Society of America Student Council.
- Aug-2020: Andy Soltisz, Heather Struckman, and Louisa Mezache selected for oral presentations at the 2020 Microscopy & Microanalysis (M&M) Conference. Louisa Mezache serves as Co-chair (Biological Sciences) to organize the 2020 M&M Pre-meeting Congress for Students and Early-career Professionals. Celine Dagher wins award for best poster presentation at the 2020 M&M Pre-meeting Congress.
- May-2020: Veeraraghavan lab awarded NIH R01 grant to uncover mechanisms of atrial fibrillation.
- May-2020: Louisa Mezache selected for oral presentation at the 2020 Heart Rhythm Society Scientific Sessions.
- Mar-2020: Louisa Mezache selected as finalist in the Cardiac Electrophysiology Society’s 2020 Young Investigator Award competition.
- Feb-2020: Struckman et al. manuscript (PMID: 31931893) published in Microscopy & Microanalysis journal; images featured on the journal cover.
- Feb-2020: Heather Struckman and Sai Veeraraghavan win separate Strategic Initiative awards from the Microscopy Society of America to pursue education-outreach.
- Jun-2019: Heather Struckman awarded NSF Graduate Student Research Fellowship
- Aug-2019: Louisa Mezache selected for oral presentation, wins Student Scholar Award at the Microscopy & Microanalysis conference.
- Feb-2019: Heather Struckman and Louisa Mezache selected for oral presentations and Louisa Mezache wins a travel award at the Annual Meeting of the Biophysical Society.
A selected list of recent publications is provided below.
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Strauss RE, Mezache L, Veeraraghavan R, Gourdie RG. The Cx43 Carboxyl-Terminal Mimetic Peptide alphaCT1 Protects Endothelial Barrier Function in a ZO1 Binding-Competent Manner. Biomolecules 2021, 11, 1192.
Moise N, Struckman HL, Dagher C, Veeraraghavan R, Weinberg SH. Intercalated disk nanoscale structure regulates cardiac conduction. J Gen Physiol. 2021. Aug 2;153(8):e202112897.
Mezache L, Struckman HL, Greer-Short A, Baine S, Györke S, Radwański PB, Hund TJ, Veeraraghavan R. Vascular Endothelial Growth Factor Promotes Atrial Arrhythmias by Inducing Acute Intercalated Disk Remodeling. Sci Rep. 2020 Nov 24.
Baine S, Thomas J, Bonilla I, Ivanova M, Li J, Veeraraghavan R, Radwański PB, Carnes C, Györke S. Muscarinic-dependent PKG phosphorylation of the cardiac ryanodine receptor is mediated by PI3K/AKT/nNOS Signaling. J Biol Chem. 2020 Jun 24.
Munger MA, Olğar Y, Koleske M, Struckman HL, Mandroli J, Lou Q, Bonilla I, Kim K, Mondragon RR, Priori SG, Volpe P, Valdivia HH, Biskupiak J, Carnes CA, Veeraraghavan R, Györke S, Radwański PB. Tetrodotoxin-sensitive neuronal-type Na+ Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation. J Am Heart Assoc. 2020 May 29.
Struckman HL, Baine S, Thomas J, Mezache L, Mykytyn K, Györke S, Radwański PB, Veeraraghavan R, Super-resolution Imaging Using Novel High Fidelity Antibody Reveals Close Association of Neuronal Sodium Channel NaV1.6 with Ryanodine Receptors in Cardiac Muscle. Microsc Microanal. 2020 Jan 14:1-9. [Journal Cover]
Bonilla IM, Belevych AE, Baine S, Stepanov A, Mezache L, Bodnar T, Liu B, Volpe P, Priori S, Weisleder N, Sakuta G, Carnes CA, Radwański PB, Veeraraghavan R*, Gyorke S. Enhancement of Cardiac Store Operated Calcium Entry (SOCE) within Novel Intercalated Disk Microdomains in Arrhythmic Disease. Sci Rep. 2019 Jul 15;9(1):10179. *Co-corresponding author
Radwański PB, Johnson CN, Györke S, Veeraraghavan R. Cardiac Arrhythmias as Manifestations of Nanopathies: An Emerging View. Front Physiol. 2018 Sep 4;9:1228.
Veeraraghavan R*, Radwański P. Sodium channel clusters: harmonizing the cardiac conduction orchestra, J Physiol. 2018 Feb 15;596(4):549-550. *Corresponding author
Veeraraghavan R*, Hoeker GS, Alvarez-Laviada A, Hoagland D, Wan X, King DR, Sanchez-Alonso J, Chen C, Jourdan J, Isom LL, Deschenes I, Smyth J, Gorelik J, Poelzing S, Gourdie RG. The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation. Elife. 2018 Aug 14. *Co-corresponding author
Koleske M, Bonilla I, Thomas J, Zaman N, Baine S, Knollmann B, Veeraraghavan R, Györke S, Radwański PB, TTX-sensitive Nav Contribute to Early and Delayed Afterdepolarizations in Long QT Arrhythmia Models, J Gen Physiol. 2018 Jul 2;150(7):991-1002.