Recently, mutations in the SH2 domain-containing protein tyrosine phosphatase Shp2, havebeen implicated in cardiac disease. Shp2 was identified as the gene mutated in -50%of cases of NoonanSyndrome (NS) and all cases of LEOPARD Syndrome (LS). NS and LS share several clinical features,including congenital heart defects, and, as such, were viewed as overlap syndromes. However, LS is NOTadisease variant of NS; LS-associated mutations in Shp2 are catalytically inactive and behave as dominantnegatives, whereas Shp2 mutations in NS are catalytically hyperactive. This proposes a model in which LSmutations are loss-of-function and NS mutations are gain-of-function. Moreover, most LS patients develop ahypertrophic cardiomyopathy (HCM), which is unique to LS; few NS patients with Shp2 mutations developHCM. The central hypothesis, therefore, is that biochemical differences between these two syndromicdisorders give rise to distinct cardiac defects. This proposal will define the mechanism(s) by which Shp2 LSmutants interfere with positive signaling events upstream and/or downstream of Ras in the Erk/MAPKpathway, will determine the signaling pathways that are aberrantly regulated by LS in the heart, will identifythe developmental interval in which Shp2 is required during cardiogenesis, and will generate and functionallyanalyze a murine model of LS. CANDIDATE: Maria Kontaridis will receive advanced training in the field ofcardiology and will further develop skills in molecular and developmental biology, biochemistry, and mousegenetics during the mentored phase of this award. Benjamin Neel, her sponsor, is an expert in Shp2 andmouse genetics. Her advisory panel (Drs. Jonathan Seidman, Jeffrey Saffitz, Lewis Cantley and JamesChang), all experts in cardiac development/pathophysiology and/or signal transduction, will contributesubstantially to her training and career development. Long-term, she plans to become an independentresearch scientist at an academic institution and to direct her own lab in cardiac development, with anemphasis on the signaling mechanisms (and mutations therein) that lead to congenital heart disease.
This work will further define the mechanisms by which genetic mutations lead to cardiacdisease. These findings will advance our knowledge of cardiac function and pathogenesis through betterunderstanding of the fundamental signaling mechanisms that mediate these processes.
| Marin, Talita M; Keith, Kimberly; Davies, Benjamin et al. (2011) Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest 121:1026-43 |
| Kontaridis, Maria I; Yang, Wentian; Bence, Kendra K et al. (2008) Deletion of Ptpn11 (Shp2) in cardiomyocytes causes dilated cardiomyopathy via effects on the extracellular signal-regulated kinase/mitogen-activated protein kinase and RhoA signaling pathways. Circulation 117:1423-35 |
