Research in my lab is focused on understanding the molecular mechanisms of cardiac contraction and the role contractile proteins play in inherited cardiomyopathies and heart failure. Muscle contraction, including contraction of the heart, occurs as the result of cyclic interactions between myosin and actin, two of the major contractile proteins found in muscle. Numerous other contractile proteins also contribute to contraction and help determine the force and speed of contraction, factors which in turn affect the strength and speed at which the heart pumps blood. Recent discoveries show that many instances of heart disease, including many instances of sudden death in otherwise young, healthy individuals, are due to defects in contractile proteins. Multiple, distinct defects in over 10 different contractile proteins have been identified that together account for a wide spectrum of disease symptoms from very mild to sudden death. Understanding how these numerous contractile proteins work together to produce force and how defects in them can ultimately lead to disease is the central research interest of my lab. To pursue these research questions we employ a combination of genetic, molecular, biochemical, and biophysical approaches. In particular, we have used gene targeting techniques to "knockout" or alter specific myofilament proteins. Structural and functional deficits produced by these genetic manipulations are then assessed using a variety of echocardiographic, histological and ultrastructural imaging, and northern and western blotting methods. Mechanical force measurements, including measurements of shortening velocity, rate of activation, and isometric tension are utilized to determine the functional effects of mutations on force in individual heart cells. Results from these studies provide a better understanding of the molecular mechanisms of muscle contraction and how defects in contractile proteins can cause altered heart function and ultimately lead to disease.
S.P. Harris, C.R. Bartley, T.A.Hacker, K.S. McDonald, P.S. Douglas, M.L. Greaser, P.A. Powers, and R.L. Moss. Hypertrophic Cardiomyopathy in Cardiac Myosin Binding Protein-C (cMyBP-C) Knockout Mice. Circulation Research, 90:594-601, 2002.
S.P. Harris, E. Rostkova, M. Gautel, and R.L. Moss. Binding of Myosin Binding Protein-C to Myosin Subfragment S2 Affects Contractility Independent of a Tether Mechanism. Circulation Research, 95:930-936, 2004.
M. Razumova, J. Shaffer, A.Y. Tu, G. Flint, M. Regnier, and S.P.Harris. Effects of the N-Terminal Domains of Myosin Binding Protein-C in an In Vitro Motility Assay: Evidence for Long-Lived Cross-Bridges. Journal of Biological Chemistry, 281:35846-35854, 2006.
J.F. Shaffer, M. Razumova, A-Y Tu, M. Regnier, and S.P. Harris. Myosin S2 is Not Required for Effects of Myosin Binding Protein-C on Motility. FEBS Letters, 581: 1501-1504, 2007.
R.W. Kensler and S.P. Harris. The Structure of Isolated Myosin Thick Filaments from cMyBP-C Knockout Mice. Biophysical Journal, 94: 1707-1718, 2008.
C.M. Jeffries, A.E. Whitten, S.P. Harris*, and J.Trewhella*. Small Angle X-Ray Scattering Reveals the N-terminal Domain Organization of Myosin Binding Protein-C. *Corresponding authors. Journal of Molecular Biology, 377: 1186-1199, 2008. Cover illustration.
M.V. Razumova, K.L. Bezold, A.Y. Tu, M. Regnier, and S.P. Harris. Contribution of the Myosin Binding Protein-C Motif to Functional Effects in Permeabilized Rat Trabeculae. Journal of General Physiology, 132: 575-85, 2008.
P.K. Luther, P.M. Bennett, C. Knupp, R. Craig, R. Padron, S.P.Harris, J. Patel, and R.L.Moss. Understanding the Organization and Role of Myosin Binding Protein-C in Striated Muscle by Analysis of Normal and MyBP-C Knockout Muscle. Journal of Molecular Biology, 384:60-72, 2008.
A.E.Whitten,C.M. Jeffries, S.P. Harris*, and J.Trewhella*. Cardiac Myosin Binding Protein-C Decorates F-Actin: Implications for Cardiac Function. *Corresponding authors. Proceedings of the National Academy of Sciences, 105:18360-5, 2008.
J.F.Shaffer, R.W. Kensler, and S.P. Harris. The Myosin Binding Protein C Motif Binds to F-Actin in a Phosphorylation Sensitive Manner. Journal of Biological Chemistry, 284:12318-12327, 2009.