Professor of Molecular and Cellular Pharmacology
Sylvester Comprehensive Cancer Center
BiographyIn my graduate and postdoctoral work, I have studied the biochemistry and biophysics of striated muscle contraction trying to understand the molecular function of almost every major sarcomeric protein. My independent research career was initiated with the inception of my first American Heart Association GIA (1998) to study HCM mutant-induced alterations in cardiac myosin RLC, followed by the three consecutive AHA GIA awards. My last AHA GIA was honored with the Robert J. Boucek, MD Research Award (2005). In 2003, I was awarded my first NIH-R01 grant and was able to launch our comprehensive studies on myosin RLC mutant-dependent development of hypertrophic cardiomyopathy (HCM). Since then, we have produced many transgenic (Tg) animal models of human disease expressing human mutations in myosin RLC and ELC and investigated their effects on myosin motor function <i>in vitro</i> and <i>in vivo.</i>
Education & Training
Teaching InterestsDr. Szczesna-Cordary’s teaching interests are in the area of molecular, and cellular mechanisms controlling the physiology of cardiac function with a focus on the regulation of the molecular motors of the heart. Specific objectives include 1) the molecular mechanisms by which thick and thin filament proteins turn on and modulate the activity of heart muscle cells, 2) alterations in this mechanism that occur during cardiac pathologies including genetic cardiomyopathies, and 3) pharmacological or small molecule manipulation of the molecular signaling process by agents acting directly or indirectly on the myofilament response to Ca<sup>2+</sup>. The approaches have made use of a broad array of technologies including 1) mutagenesis, expression, purification, and <i>in vitro</i> reconstitution of myosin subunits (myosin light chains) combined with measurements of regulation of force and energy coupling, 2) transgenesis using overexpression of myofilament proteins including myosin RLC, and ELC, 3) in situ and <i>in vitro</i> determination of cardiac function employing isolated cardiomyocytes (muscle fibers), and <i>in situ</i> heart function.
Research InterestsThe general research interests of my laboratory focus on striated (skeletal and cardiac) muscle contraction and the mechanisms that control force generation in muscle and work in parallel with the Ca2+-dependent regulatory system, tropomyosin (Tm), and troponin (Tn). Calcium-binding to the thin filament is the major element controlling active force in muscle, but other processes regulate contractile force and sarcomere shortening. In particular, we are interested in the regulation of contraction by the myosin regulatory (RLC) and essential (ELC) light chains encoded by <i>MYL2</i> and <i>MYL3</i> genes, respectively. Myosin-II is an actin-dependent molecular motor that uses chemical energy derived from Mg·ATP hydrolysis to produce mechanical work and filament movement. Both myosin light chains (RLC and ELC) constitute an essential part of the myosin molecule by supporting the neck region (lever arm) of the myosin head (cross-bridge) but they also contribute to the regulation of the acto-myosin ATPase cycle and the power stroke. We hypothesize that both myosin light chains interact with the myosin heavy chain (MHC) to provide structural stability to the myosin lever arm and support its function in propagating the conformational changes from the motor domain to the myosin backbone and in the transmission of external loads to the myosin active site.<br> <br>The importance of both myosin light chains has been highlighted by the identification of about 30 missense mutations in <i>MYL2</i> and <i>MYL3 </i>genes in patients suffering from familial Hypertrophic (HCM), Dilated (DCM), or Restrictive (RCM) Cardiomyopathy.<br> <br>Using transgenic mouse models of human HCM, DCM, or RCM, the Szczesna-Cordary Lab is studying the biomechanics of heart muscle from the organ down to the molecular level employing a combination of physiological, hemodynamic, and molecular approaches. The research work has predominantly focused on identifying novel mechanisms and validating new targets and/or treatments to battle cardiomyopathy and heart failure. These studies have been a very rich source of information for a variety of aspects of myosin light chain-induced cardiomyopathy providing mechanistic insight into this highly detrimental cardiac disease. We have already reached the next step and are making our findings applicable in translational research experiments developing target-specific therapeutic approaches.
Grants & Sponsored Research
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