James Smyth, Ph.D.
Exploring intercellular communication
How does heart disease undermine how cells connect to keep the heart beating?
When cells in the heart and other organs can’t communicate effectively, they dangerously inhibit organ system function, sometimes with fatal consequences. These alterations are associated with a broad array of human diseases affecting the heart and nervous system as well as cancer progression. The Smyth Laboratory probes the mechanisms of cardiomyopathy at the subcellular level. The objective is identifying new targets for therapeutic interventions to restore normal cardiac function to diseased hearts.
One of the most important mechanisms of intercellular communication is through structures known as gap junctions, which are formed by proteins and directly couple cell interiors. 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 proper beating of the heart. In most forms of heart disease, altered expression of Cx43 interferes with the heart’s electrical system, fostering arrhythmia and sometimes triggering sudden cardiac death.
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, Smyth Lab researchers determine the molecular changes that occur during disease responsible for reduced gap junction formation. They investigate how regulation of protein synthesis, at the point of mRNA translation influences 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.
- Associate Professor, Fralin Biomedical Research Institute at VTC
- Associate Professor, Department of Biological Sciences, College of Science
- Associate Professor, Department of Basic Science Education, School of Medicine
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).
University of California, San Francisco
Cedars-Sinai Heart Institute, Los Angeles
- Trinity College Dublin: Ph.D., Virology
- University of California, San Francisco: Postdoctoral fellowship
- University College Dublin: B.S., Microbiology
- 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