ANIMAL MODELS OF HYPERTROPHIC CARDIOMYOPATHY

Children'S Hospital Med Ctr (Cincinnati), Cincinnati OH

Investigators

Linked publications & trials

Abstract

DESCRIPTION: (Adapted from the Investigator's Abstract) Familial hypertrophic cardiomyopathy, a major cause of sudden death, is caused by mutations in the genes encoding various components of the cardiac contractile apparatus. The applicant proposes to use a combination of molecular, genetic and functional approaches to understand the pathological processes that occur in the heart as a result of the expression of the mutant proteins in patients with FHC. Using the technique of cardiac specific transgenic overexpression, specific contractile protein isoforms in the cardiac compartment can be replaced in transgenic animals and thereby the functional consequences of the mutations over the lifetime of the animal can be established. Specifically, four constructs will be used, each of which contains a mutation in the sequence known to be associated with FHC:. ELC (essential light chain) (MET 149 VAL), MLC regulatory light chain (GLU 22 LYS), the ILE79ASN mutation in cardiac troponin T, and the truncation mutation in MHC binding protein C (delta 845-1189). The dose-dependent consequences of the expression of these mutant proteins will be studied by analyzing multiple transgenic lines. A rabbit model of FHC will be generated using the two light chain constructs, since rabbit heart is more representative of the human organ. The data to be obtained from the rabbit lines when compared with the ongoing mouse studies will allow an assessment of the murine models applicability to the large animal heart and together these models should prove to be invaluable in increasing our understanding of how the primary genetic etiology contributes to the developing hypertrophic response.