MECHANISMS OF CARDIAC PATHOGENESIS IN NOONAN SYNDROME

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Mutations in PTPN11 cause Noonan syndrome. Component 4 will explore the mechanistic underpinnings of PTPN11's role in valve formation. The objective is to mechanistically dissect the cardiac-autonomous pathologies of Noonan syndrome. Our immediate goals are to carry out comprehensive studies using inducible, cardiac-specific expression of both the normal and mutated forms of the tyrosine phosphatase, SHP-2 in the different cardiac cell populations. These studies will be complemented by an inducible, cardiac-specific gene ablation of PTPN11 in order to discern protein function at different developmental times. SPECIFIC AIM 1 will explore the cardiomyocyte autonomous effects of SHP-2 expression in order to dissect the primary and secondary effects on hypertrophy and valve dysfunction. Wild type (WT) and mutated protein will be expressed only in the cardiomyocyte population via transgenesis. The hypothesis is that expression of the Noonan mutation SHP-29(Gln79Arg), will result in cardiomyocyte hypertrophy. SPECIFIC AIM 2 will carry out the complementary studies in the relevant non-cardiomyocyte populations to define the role that the SHP-2 mutation plays during cardiac cushion formation and development of the outflow tract. Both the WT and mutated protein will be expressed during development in the endothelial population only. SPECIFIC AIM 3 will explore loss of function of the normal protein by carrying out art inducible, cardiomyocyte-specific knockout using the MerCreMer system developed in our Division. We hypothesize that the effects of SHP-2 loss of function will differ radically depending upon the developmental time and in this manner the role of SHP-2 in controlling normal cellular processes in the heart can be explored. SPECIFIC AIM 4 will explore the signaling pathways downstream of SHP-2 in cardiomyocytes. We hypothesize that SHP-2 signals through activation of the MAP kinase (MAPK) pathway in cardiomyocytes and that ablation of SHP-2 will blunt MAPK signaling while over-expression of WT-SHP-2 or SHP-2(Gln79Arg) will result in increased MAPK activity or inappropriate MAPK activity through the ERK branch in response to various stimuli.