Idiopathic dilated cardiomyopathy (IDC), resulting in an enlarged heart that does not pump properly, is a common disease (~ 1:2500) associated with an annual mortality rate of greater than 10000 deaths. These statistics underscore the significance for developing new therapeutic strategies aimed at understanding, preventing, arresting or reversing progressive cardiac dysfunction. However, to date, the cause(s) of IDC is (are) unclear and the molecular signaling mechanisms that are aberrantly regulated in IDC are largely unknown. Our proposal will determine whether aberrant regulation of the small GTPase RhoA by the protein tyrosine phosphatase Shp2 is directly involved in mediating IDC pathogenesis. Our recently published work shows that hearts from mice with cardiomyocyte-specific deletion of Shp2, a key positive regulator in most, if not all, receptor tyrosine kinase (RTK) signaling pathways, develop a severe dilated cardiomyopathy (DCM). This loss of Shp2 also revealed a hyper-activation in the RhoA signaling pathway, implicating a novel, yet undefined, connection between Shp2 and the RhoA signaling pathway in the heart. We hypothesize that suppression of RhoA activity, via Shp2, is cardioprotective and, as such, is biochemically required to prevent IDC and heart failure. RhoA is a small GTP binding protein involved in important cellular functions including cell proliferation, migration and cytoskeletal reorganization. Recent translational work has demonstrated a significant role for RhoA in cardiovascular disease, including hypertension and atherosclerosis;however, here too, the underlying mechanisms are unclear. In this proposal, we will elucidate the mechanisms by which RhoA is regulated by Shp2. This proposal addresses several interesting and key questions with regards to the function of RhoA in cardiomyocyte disease. Using a combined, comprehensive set of biochemical, cell biological, proteomic and genetic approaches, we plan to (1) determine the physiological significance of loss of RhoA activity in the adult myocardium (2) determine whether loss of RhoA expression and/or activity can rescue the functional cardiac defects in Shp2 deleted mice in vivo, and (3) utilize proteomic and in vitro and ex vivo biochemical approaches to examine the mechanism by which Shp2 regulation of RhoA affects RTK signaling in the myocardium. Results of this proposal will elucidate the mechanism(s) by which RhoA activity is regulated in the adult myocardium, reveal the manner in which Shp2 regulation of RhoA activity may be cardioprotective, and assist in the generation of novel, molecular-based pharmacological targets for the treatment of heart failure in patients with IDC.
Information gained from these studies will 1) elucidate the mechanism(s) by which RhoA activity is regulated in the adult myocardium;2) reveal the manner in which Shp2 regulation of RhoA activity may be cardioprotective, which, in turn, will create new avenues of research for IDC and heart failure;and 3) by elucidating the RhoA-mediated signaling pathways and molecules that regulate cardiac pathogenesis, will assist in the generation of novel, molecular-based pharmacological targets for the treatment of heart failure in patients with IDC.
|Wang, Jianxun; Mizui, Masayuki; Zeng, Li-Fan et al. (2016) Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus. J Clin Invest 126:2077-92|
|Lauriol, Jessica; Cabrera, Janel R; Roy, Ashbeel et al. (2016) Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines. J Clin Invest 126:2989-3005|
|Breitkopf, Susanne B; Yang, Xuemei; Begley, Michael J et al. (2016) A Cross-Species Study of PI3K Protein-Protein Interactions Reveals the Direct Interaction of P85 and SHP2. Sci Rep 6:20471|
|Hahn, Andreas; Lauriol, Jessica; Thul, Josef et al. (2015) Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog. Am J Med Genet A 167A:744-51|
|Lauriol, Jessica; JaffrÃ©, Fabrice; Kontaridis, Maria I (2015) The role of the protein tyrosine phosphatase SHP2 in cardiac development and disease. Semin Cell Dev Biol 37:73-81|
|Paardekooper Overman, Jeroen; Yi, Jae-Sung; Bonetti, Monica et al. (2014) PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice. Mol Cell Biol 34:2874-89|
|Lauriol, Jessica; Keith, Kimberly; JaffrÃ©, Fabrice et al. (2014) RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis. Sci Signal 7:ra100|
|Kontaridis, Maria I (2014) How to get a K award: it is not just about the science. Circ Res 114:941-3|
|Dolmatova, Elena; Spagnol, Gaelle; Boassa, Daniela et al. (2012) Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation. Am J Physiol Heart Circ Physiol 303:H1208-18|
|Lauriol, Jessica; Kontaridis, Maria I (2011) PTPN11-associated mutations in the heart: has LEOPARD changed Its RASpots? Trends Cardiovasc Med 21:97-104|
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