James Smyth, Ph.D.
Assistant Professor, Virginia Tech Carilion Research Institute
Assistant Professor, Center for Heart and Regenerative Medicine Research, Virginia Tech Carilion Research Institute
Assistant Professor of Biological Sciences, College of Science, Virginia Tech
Assistant Professor of Biomedical Science, Virginia Tech Carilion School of Medicine
The Smyth Laboratory aims to understand mechanisms of cardiomyopathy at the subcellular level with the objective of identifying new targets for therapeutic interventions aimed at restoring normal cardiac function to diseased hearts.
Direct intercellular communication is essential for all organ systems to function, and alterations in this important process are associated with a broad array of human diseases, including those affecting the heart and nervous system, in addition to cancer progression. One of the most important mechanisms of intercellular communication is through structures known as gap junctions, which directly couple cell interiors to one another.
Gap junctions are formed by connexin proteins, and in the working myocardium of the cardiac ventricle, connexin 43 (Cx43) is the primary isoform. These Cx43 gap junctions electrically couple cardiac muscle cells and are responsible for the well-orchestrated propagation of action potentials through the heart to induce contraction. In most forms of heart disease, altered expression of Cx43 results in improper or reduced electrical coupling, creating a dangerous substrate prone to arrhythmia and responsible for sudden cardiac death.
Many factors can precipitate cardiomyopathies. The Smyth Laboratory uses molecularly tractable model systems to understand how the heart responds to injury from localized infarctions and ischemia, to infection of the heart by viruses, such as adenovirus.
Using state-of-the-art molecular, biochemical, and imaging technologies, researchers are determining the molecular changes that occur during disease responsible for reduced gap junction formation. We are investigating how regulation of protein synthesis, at the point of mRNA translation, can generate multiple truncated isoforms of Cx43, which can, in turn, influence gap junction formation.
This emerging field of alternate translation initiation is subject to dynamic regulation through signal-transduction networks in the cell, which scientists are interrogating biochemically. Live-cell fluorescence confocal microscopy enables us to watch these events in real time and understand how cardiac cells respond to such stresses as hypoxia and viral infection. With super-resolution microscopy, researchers are also probing connexin biology at a resolution of 20 nanometers, providing previously unattainable and exciting insights at the molecular level.
For a more complete listing of James Smyth’s publications, visit PubMed.
Education and Training
- University of California, San Francisco: Postdoctoral fellowship
- Trinity College Dublin: PhD, Virology
- University College Dublin: BS, Microbiology
- University of California, San Francisco
- Cedars-Sinai Heart Institute, Los Angeles
Awards and Honors
- Travel Award and Highly Commended Poster Presentation, Gordon Research Conference on Cardiac Arrhythmia Mechanisms, 2013
- Trainee Oral Presentation Award, Second Prize, International Gap Junction Conference, 2013
- Smyth JW, Zhang SS, Sanchez JM, Lamouille S, Vogan JM, Hesketh GG, Hong T, Tomaselli GF, Shaw RM. (2014). A 14-3-3 mode-1 binding motif initiates gap junction internalization during acute cardiac ischemia. Traffic 15(6): 684-699.
- Smyth JW, Shaw RM. (2013). Autoregulation of connexin43 gap junction formation by internally translated isoforms. Cell Reports.
- Hong TT, Smyth JW, Chu KY, Vogan JM, Fong TS, Jensen BC, Fang K, Halushka MK, Russell SD, Colecraft H, Hoopes CW, Ocorr K, Chi NC, Shaw RM. (2012). BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes. Heart Rhythm 9(5).
- Smyth JW, Vogan JM, Buch PJ, Zhang SS, Fong TS, Hong TT, Shaw RM. (2012). Actin cytoskeleton rest stops regulate anterograde traffic of connexin 43 vesicles to the plasma membrane. Circulation Research 110(7).
- Smyth JW, Hong TTH, Gao D, Vogan J, Jensen B, Fong T, Simpson P, Stainier D, Chi N, Shaw RM. (2010). Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium. The Journal of Clinical Investigation 120(1): 87-9.