Research Interests

Muscle contraction is defined by the cyclical interaction between actin and myosin. The regulation of this interaction is governed by the troponin complex in striated muscles and myosin light chain phosphorylation in smooth muscles. During pathophysiological conditions, efficient regulation of muscle contraction may be compromised, defining the background for cardiomyopathies and hypertension. Along these lines, current areas of research interest include:

Characterizing the actomyosin crossbridge cycle during ischemia â?? reperfusion, specifically focusing on changes in muscle mechanics and regulatory protein function.

Ischemia - reperfusion is accompanied by changes in the contractility of the heart. The decrease in contractility is often attributed to a reduction in ATP availability, compromising the function of the myosin ATPase. However, preliminary data suggests that the decline in contractility with ischemia may be related to intrinsic changes to the regulatory thin filament that limit contractility independent of ATP availability. Changes in cell redox state or aberrant second messenger signals during ischemia - reperfusion is hypothesized to result in post-translational modification of regulatory proteins, such as actin glutathionylation or troponin I phosphorylation, to alter contractility through mechanisms independent of ATP availability. Techniques to address these questions involve working models of ischemia - reperfusion, measurements of isometric / isotonic fibre contraction, as well as molecular and biochemical approaches to define changes in protein function.

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Examining the role of the actin - associated thin filament regulatory complex in striated muscle contractility.

The regulation of the actomyosin crossbridge cycle in striated muscles involves Ca2+-dependent relief of troponin - tropomyosin inhibition. However, two additional proteins in striated muscles, nebulin and titin, also line the actin filament and may define additional regulatory or mechanical properties for the sarcomere. Currently, the involvement of nebulin and titin in the troponin - tropomyosin dependent regulation of striated muscle contraction is unclear. Using in vitro reconstituted actomyosin ATPase systems, the contribution of nebulin and titin motifs to striated muscle regulation is being explored.

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The role of protein kinase G in cardiovascular function.

The activation of protein kinase G (PKG) in smooth muscles is a physiologically relevant pathway mediating vasodilatation. However, the effects of PKG activation on the contractility of cardiac muscles are not as well studied. Initial research efforts have determined that cGMP-mediated activation of PKG results in a change in the crossbridge cycling rate as determined by permeabilized fibre experiments. Current research efforts are aimed at defining the transition of the actomyosin crossbridge cycle influenced by PKG activation, as well as identifying relevant targets for PKG in the contractile filaments of cardiac muscles. A variety of molecular, biochemical and biophysical methods are used to address the research question.

In addition, PKG is involved in the calcium-sensitization pathway during smooth muscle activation. This function is governed by an interaction of PKG with the myosin targeting subunit (MYPT) of the smooth muscle myosin phosphatase. In collaboration with Dr. Frank Brozovich, the important domains of MYPT involved in the interaction with PKG are being mapped.

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