David M. Warshaw, MD

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Biography:

Dr. David Warshaw is Chair of the Department of Molecular Physiology & Biophysics at the University of Vermont.  He is both a Fellow and Established Investigator of the American Heart Association and serves on committees for the Biophysical Society. He is a member of the editorial boards of prestigious scientific journals and has been honored by chairing and organizing international scientific meetings in the area of cardiac and vascular smooth muscle research. He is the Principle Investigator of a Program Project Grant from the National Institutes of Health (NIH) dealing with a genetic form of heart failure, Familial Hypertrophic Cardiomyopathy. He serves on NIH grant application review panels. He has a productive active laboratory that studies the molecular basis of power generation in the heart by focusing on the structure and function of protein molecular motors (i.e. myosin) that generate the force and motion of the heart.

Major Research Interests:

Smooth and cardiac muscle contraction are essential to the normal functioning of the cardiovascular system. The two types of muscle share a common contractile mechanism that involves the cyclic interaction between myosin, a molecular motor, and actin to generate force and motion. Smooth muscle myosin has been shown to be a high force generating motor with the use of an in vitro motility assay to assess the molecular mechanics of the actomyosin interaction. As judged from results of these studies, smooth muscle myosin generates 3-4 times the average force of striated muscle myosins. This enhanced force generating capacity may relate to structural differences between the myosin isoforms. Using the Baculovirus/insect cell system in collaboration with Dr. Kathleen Trybus in his department, Drs. Warshaw and Trybus express mutant smooth muscle myosin that probe the molecular domains of the myosin molecule and the effects these mutations have on myosin’s molecular performance. Myosin’s molecular mechanics are assessed with a state-of-the-art laser optical trapping technique that can measure the molecular forces and displacements generated by a single myosin molecule as it interacts with a single actin filament. These studies should identify which molecular domains of the smooth muscle myosin molecule contribute to its enhanced force generating capacity compared with striated muscle myosins.

Using a similar approach, Dr. Warshaw investigates the effects of single point mutations in either cardiac muscle myosin or actin that are the cause for sudden death in humans afflicted with either Familial Hypertrophic Cardiomyopathy (FHC) or Dilated Cardiomyopathy (DCM). In collaboration with Dr. Jonathan Seidman at Harvard University and Dr. Jeffrey Robbins at the University of Cincinnati, mutant cardiac myosin expressed in transgenic mice are assessed both in a simplified model system for muscle contraction and with the laser trap technique. These studies will allow assessment of myosin structure:function relationships at a molecular level and elucidate a molecular basis for the sequelae of these deadly diseases.

Recently, Dr. Warshaw has developed a total internal reflectance fluorescence microscope that is capable of monitoring fluorescence polarization changes from a single fluorophore. The goal of this development is to label a single myosin molecule at a specific site with a fluorescent probe and to then monitor changes in the orientation of the probe during the myosin powerstroke. By marrying this new technique with the laser trap, he proposes to characterize myosin structure:function in real time at the single molecule level. In aggregate, his studies should provide significant insight into the molecular mechanism by which myosin converts chemical energy from ATP hydrolysis into mechanical work.

Active Grant Support

Grant Title: Familial Hypertrophic Cardiomyopathy:  Sarcomeric Disease.
Sponsor: National Institutes of Health
PI: Dr. David Warshaw

Grant Title: Mechanics and Enzymology of a Single Myosin Motor.
Sponsor: National Institutes of Health
PI: Dr. David Warshaw

Grant Title: Cardiac Myosin Transgenesis:  Molecular Design Performance.
Sponsor: National Institutes of Health
Co-Investigator: Dr. David Warshaw; Dr. Norman Alpert (PI)

Grant Title: Molecular Mechanics of FHC & DCM Mutant Actomyosin
Sponsor: National Institutes of Health
Sponsor: Dr. David Warshaw

Grant Title: Postdoctoral Cardiovascular Research Training Program
Sponsor: National Institutes of Health
Co-Investigator: Dr. David Warshaw; Dr. Martin M. LeWinter (PI)

Grant Title: Postdoctoral Training Program in Molecular Basis of Cardiovascular Function
Sponsor: National Institutes of Health
Co-Investigator: Dr. David Warshaw

Publications:

Representative Publications From a Total of 70

Warshaw, D. and F. Fay. Tension transients in single isolated smooth muscle cells. Science. 219:1438-1441, 1983.

Warshaw, D.M., W. McBride, S. Work.  Corkscrew-like shortening in single smooth muscle cells. Science 236:1457-1459, 1987.

Warshaw, D.M., J.M. Desrosiers, S.S. Work and K.M. Trybus.  Smooth muscle myosin cross-bridge interactions modulate actin filament sliding velocity in vitro. J. Cell Biol. 111:453-463, 1990.

VanBuren, P., S.S. Work, and D.M. Warshaw.  Enhanced force generation by smooth muscle myosin in vitro.  PNAS 91:202-205, 1994.

Tyska, M.J., E. Hayes,  M. Giewat, C.E. Seidman, J.G. Seidman and D.M. Warshaw.  Single molecule mechanics of R403Q mutant cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy. Circ Res. 86:737-744, 2000.

Sanbe, A., J. Gulick, E. Hayes, D.M.Warshaw, H. Osinska, C-B Chan, R. Klevitsky, and J. Robbins. Myosin light chain replacement in the heart.  Am. J. Physiol. 279:H1355-H1364, 2000.

Alpert, N.R., Brosseau, C., Federico, A., Krenz, M., Robbins, J., and D.M.Warshaw. Molecular mechanics of mouse cardiac myosin isoforms.  Am J Physiol Heart Circ Physiol. 283(4):H1446-54, 2002.

Krenz, M., A. Sanbe, F. Bouyer-Dalloz, J. Gulick, R. Klevitsky, T.E. Hewett, H.E. Osinska, J.N. Lorenz, C. Brosseau, A. Federico, N.R. Alpert, D.M. Warshaw, M.B. Perryman, S.M. Helmke, and J. Robbins.  Analysis of myosin heavy chain functionality in the heart.  J B iol Chem 278:17466-17474, 2003.

Kad, N.M., J.B., Patlak, P.M. Fagnant, K.M. Trybus, and D.M. Warshaw.  Mutation of a conserved clycine in the SH1-SH2 helix affects the load-dependent kinetics of myosin.  Biophys J 92:1623-1631, 2007.

Ali, M.Y., E.B. Krementsova, G.G. Kennedy, R. Mahaffy, T.D. Pollard, K.M. Trybus, and D.M. Warshaw.  From the Cover:  Myosin Va maneuvers through actin intersections and diffuses along microtubules.  Proc Natl Acad Sci USA 104:4332-4336, 2007.