The long-term goal of this work is to establish a unifying primary mechanism of cardiomyopathy pathogenesis. Hypertrophic cardiomyopathy (HCM) is defined as a disease of the sarcomere. Patients with HCM have diastolic dysfunction with normal or supra-normal systolic function. In comparison, dilated cardiomyopathy (DCM) patients present with diminished contractile function and ventricular chamber dilation. Unexpectedly, DCM and HCM share in common six sarcomeric genes as disease loci. It is presently unknown how mutations in identical genes can result in the divergent functional outcomes of DCM and HCM. In addition, recent study shows that restrictive cardiomyopathy (RCM), a disease of the myocardium characterized by restrictive filling with normal or decreased ventricular volume, can be caused by mutations in troponin I. The working hypothesis of this proposal is that distinct primary alterations in myocyte contractile performance result from specific mutations within the same or different sarcomeric gene(s), and this underlies, at least in part, the variable clinical phenotypes in hypertrophic cardiomyopathy, dilated cardiomyopathy, and restrictive cardiomyopathy. The experimental plan involves an array of high-fidelity single cardiac myocyte functional assays including a novel carbon-fiber-based technique to directly determine force and power output under physiological loads in living adult cardiac myocytes.
The Specific Aims are:
Aim 1. To determine the primary defect(s) caused by RCM-associated single missense mutations in cTnl. Hypothesis: RCM mutants will incorporate normally into the adult cardiac myocyte sarcomere and have a dominant effect to alter myocyte contractile performance.
Aim 2. To determine whether specific DCM and HCM mutations in tropomyosin (Tm) and cardiac troponin T (cTnT) will produce specific and distinct differences in cardiac myocyte performance. Hypothesis: DCM mutations in Tm and cTnT will decrease twitch force and power output, and hasten relaxation performance. HCM mutants will have opposite effects.
| Davis, Jennifer; Wen, Haitao; Edwards, Terri et al. (2008) Allele and species dependent contractile defects by restrictive and hypertrophic cardiomyopathy-linked troponin I mutants. J Mol Cell Cardiol 44:891-904 |
| Herron, Todd J; Vandenboom, Rene; Fomicheva, Ekaterina et al. (2007) Calcium-independent negative inotropy by beta-myosin heavy chain gene transfer in cardiac myocytes. Circ Res 100:1182-90 |
