The Smyth Laboratory, led by James Smyth, Ph.D., studies cardiomyopathy at a subcellular level, searching for potential targets for therapeutic interventions to help restore 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.