Bruce D. Gelb, MD
Hypertrophic Cardiomyopathy and RAS-MAP Kinase Signaling
Mount Sinai School of Medicine, New York, NY
2008 Amount Awarded – $49,587
Hypertrophic cardiomyopathy, the condition in which there is an excess of heart muscle, is a serious cardiac condition that can lead to illness and death. In adults, most cases are caused by mutations in genes for the structural protein in heart muscle cells. In infants and younger children, the causes are different with a genetic condition called Noonan syndrome predominating after infancy. The principal investigator's group recently identified a new gene for Noonan Syndrome in which children with mutations in this gene, called RAF1, are highly likely to develop hypertrophic cardiomyopathy. This proposal includes two sets of studies aimed at understanding how RAF1 mutations cause hypertrophic cardiomyopathy as a steppingstone to the development of novel treatments to prevent or ameliorate it. The first goal will be to introduce a mutation into the Raf1 gene in mice. This is likely to replicate the human disease and permit studies of the heart as it hypertrophies. The second goal will be to introduce mutant RAF1 genes into rat heart muscle cells in cell culture. Again, this is likely to engender cardiac hypertrophy that can be characterized biochemically. Taken together, the proposed work will provide new insights into the manner in which certain RAF1 mutations result in cardiac hypertrophy. Aside from its relevance to children with Noonan syndrome, this work will have broader impact on our understanding of how the heart responds to certain hypertrophic stimuli normally or pathologically.