Our goal is to understand the fundamental molecular motions and interactions that are responsible for cellular movement, to determine the molecular bases of muscle disorders, and to devise novel therapies based on these discoveries. We approach this multidisciplinary problem with a wide range of techniques — physiology, enzyme kinetics, molecular genetics, peptide synthesis, computer simulation — but our forte is site-directed spectroscopic probes.
After attaching probes (spin labels, fluorescent dyes, phosphorescent dyes, or isotopes) to selected muscle proteins in solution or in cells, we perform magnetic resonance or optical spectroscopy to directly detect the motions of the force-generating proteins, actin and myosin, or the membrane ion pumps and channels responsible for muscle excitation and relaxation. These same tools are then used to test the efficacy of gene or drug therapies designed to treat heart failure or muscular dystrophy.
Our research involves several types of muscle, but the laboratory focuses increasingly on the heart. Indeed, our newest and most exciting direction is to use the principles of structural biophysics to design new molecular therapies for heart failure. This is an extremely ambitious and high-risk goal, but we are in a unique position to achieve it, due to an unparalleled combination of technologies, insights, and expert collaborators. As a result of these advances, we have started a company, Photonic Pharma LLC (https://www.photonicpharma.com/), with the goal of commercializing our discoveries in the field of drug discovery. 1 min video.
Schaaf, T. M., E. Kleinboehl, S. L. Yuen, L. N. Roelike, B. Svensson, A. R. Thompson, R. L. Cornea, and D. .D. Thomas. 2020. Live-Cell Cardiac-Specific High-Throughput Screening Platform for Drug-Like Molecules that Enhance Ca2+ Transport. Cells 9:1170.
Olivieri, C., Y. Wang, G. C. Li, V. S. Manu, J. Kim, B. R. Stultz, M. Neibergall, F. Porcelli, J. M. Muretta, D. D. Thomas, J. Gao, D. K. Blumenthal, S. S. Taylor, and G. Veglia. 2020. Multi-state recognition pathway of the intrinsically disordered protein kinase inhibitor by protein kinase A. eLife 9:e55607.
Rebbeck, R. T., D. P. Singh, K. A. Janicek, D. D. Thomas, D. M. Bers, B. S. Launikonis, and R. L. Cornea. 2020. RyR1-targeted drug discovery pipeline integrating FRET-based high-throughput screening and human myofiber dynamic Ca2+ assays. Nature Scientific Reports 10:1791.
Lindsay, A. L., C. W. Baumann, R. T. Rebbeck, S. L. Yuen, M. W. Southern, J. S. Hodges, R. L. Cornea, D. D. Thomas, J. M. Ervasti, and D. A. Lowe. 2020. Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators. Skeletal Muscle 10:3.
McCarthy, M. R., Y. Savich, R. L. Cornea, and D. D. Thomas. 2020. Resolved structural states of calmodulin in regulation of skeletal muscle calcium release. Biophys J 118, 1090-1100.
Stroik, D. R., D. K. Ceholski, P. A. Bidwell, J. Mleczko, P. F. Thanel, F. Kamdar, J. M. Autry, R. L. Cornea, and D. D. Thomas. 2020. Viral expression of a SERCA2a-activating PLB mutant improves calcium cycling and synchronicity in dilated cardiomyopathic hiPSC-CMs. J Mol Cell Cardiol 138:59-65.
Martin, P. D., B. Svensson, D. D. Thomas, and S. Stoll. 2019. Trajectory-based simulation of EPR spectra: models of rotational motion for spin labels on proteins. J Phys Chem B 123:10131-10141.
Lo, C. H., T. M. Schaaf, B. D. Grant, C. K. W. Lim, P. Bawaskar, C. C. Aldrich, D. D. Thomas, and J. N. Sachs. 2019. Noncompetitive inhibitors of TNFR1 probe conformational activation states. Sci Signal 12:eaav5637.
Binder, B. P., A. R. Thompson, and D. D. Thomas. 2019. Atomistic models from orientation and distance constraints using EPR of a bifunctional spin label. Biophys J 117:319-330.
Savich, Y., B. P. Binder, A. R. Thompson, and D. D. Thomas. 2019. Myosin lever arm orientation in muscle determined with high angular resolution using bifunctional spin labels. J Gen Physiol 151 (8): 1007–1016.