The overall focus of our research has been on the biological interactions which are central to the control of biological function; attempting to relate protein structure, kinetics, dynamics, and thermodynamics to function.
Heart disease is the leading cause of death in western society for men and women. The long term focus of our program is the elucidation of the molecular details of the calcium mediated thin filament based regulation of contraction in cardiac and skeletal muscle. Recent discoveries have seen a great expansion in the number of sacromere proteins, concomitant appreciation of the interconnected cytoskeletal network critical for contractile activity, and a recognition of a large number of mutations in these cytoskeletal components which account for a number of human myopathies. Of special medical importance because of the prevalence of cardiovascular disease are the cardiac regulatory proteins, where phosphorylation of cardiac troponin plays a major role in mediating myofilament physiology; troponin mutations are implicated in various cardiac diseases including familial hypertrophic cardiomyopathy which are amongst the most frequently occurring inherited cardiac disorders; troponin proteins are important markers of cardiovascular damage; and cardiac troponin is subject to influence by cardiotonic drugs, which may be used to modulate the calcium response of the myofilaments in diseased hearts. Thus, there is a strong interest and need in understanding the structure and dynamics of these proteins.
Most of our research involves the determination of the solution structure and dynamics of muscle proteins using high field, multinuclear, multidimension Nuclear Magnetic Resonance spectroscopic techiques. For a recent review of some of our work see: Li MX, Wang X, Sykes BD., J Muscle Res Cell Motil. 2004;25(7):559-79. Structural based insights into the role of troponin in cardiac muscle pathophysiology.
We are also developing new solid state NMR techniques for the determination of the orientation and in situ structures of the thin filament regulatory proteins in intact muscle fibers. This will allow us to connect high resolution structural and dynamic changes to physiological and functional measurements (i.e., force).