Abdur Razzaque, PhD
Mechanism of RAF1 Mediated Pediatric Hypertrophic Cardiomyopathy
University of Wisconsin, Madison, WI
2015 Amount Awarded – $48,000
Hypertrophic cardiomyopathy (HCM) is commonly observed in 15-25% of the pediatric patients with Noonan syndrome (NS), an autosomal dominant disorder. Previously, gain-of-function RAF1 gene mutations in NS were identified specifically in patients with HCM. It also was found that growth hormone treatment exacerbates HCM in patients with a specific RAF1 mutation (S257L). RAF1 is a mitogen-activated protein kinase that plays a central role in the signaling pathway regulating the induction of genes that determine the biological response of the cells, including cardiac hypertrophy. In vitro studies show that because of the gain-of-function activity, the RAF1 mutation dysregulates the signaling pathway that causes HCM in pediatric patients. By analyzing genetically engineered mice and using pharmacologic inhibitors, this study will 1) determine the effect of RAF1 mutation in cardiac cells and its contribution to the development of HCM, 2) determine the cellular mechanism(s) of how the RAF1 mutation leads to HCM and 3) analyze the effect of growth hormone in the hypertrophic heart. These findings will provide novel insights into the function of RAF1 and its mutations in the development of HCM in children. Understanding the exact cellular mechanism(s) caused by this gene dysfunction and the effect of growth hormone on HCM help to improve medical management and to develop new treatment strategies for pediatric HCM patients.