Our lab uses multinuclear multidimensional nuclear magnetic resonance (NMR) spectroscopy to study proteins at the molecular level. We currently have four areas of interest:
1) Structure and function of the cardiac troponin complex. The protein troponin complex is the dynamic switch that turns muscle contraction on and off in response to calcium transients in both cardiac and skeletal muscle. Some of the most important regions of the troponin complex have eluded structural characterization because of their flexible, mobile character, fitting for a switch that has to alternate between "on" and "off" states. NMR spectroscopy is the ideal method for studying these regions in atomic level detail, necessary for understanding how troponin fulfills its biologic role and how it is modulated by post-translational modifications and cardiomyopathy-causing mutations.
2) Refining the troponin assay. The serum troponin assay is the gold standard for diagnosing myocardial infarction, and high sensitivity assays are now capable of detecting troponin in the serum of health people as well. Serum troponin is a heterogeneous mixture, and there is poor agreement in quantitation between different commercial manufacturers of the assay. We aim to determine the reasons behind these differences and to determine if the different forms of troponin can yield additionally useful information about patients.
3) Developing drugs that target troponin to treat systolic heart failure. Systolic heart failure is caused by an inability of the heart to contract forcefully enough to satisfy the metabolic demands of the body. One current failing of modern pharmacotherapy is the lack of a positive inotrope (a compound that increases contractility) that is safe and effective. A troponin activating drug could in theory fulfill this role. We are developing troponin activator compounds in collaboration with organic chemists, computational chemists, and cardiac physiologists.
4) Developing NMR methodology for high molecular weight systems. We are also interested in developing new protein isotope labeling schemes in E. coli and new NMR pulse sequences to extend solution NMR spectroscopy to higher molecular weight systems like membrane proteins.
Targeting the cardiac troponin complex for the treatment of the heritable cardiomyopathies
- Funding Source: Canadian Institutes of Health Research
- Year Granted: 2017