BBS Faculty Member - Maria Kontaridis

Maria Kontaridis

Department of Cardiology

Beth Israel Deaconess Medical Center
Center for Life Sciences Building, Room 908
3 Blackfan Circle
Boston, MA 02115
Tel: 617-735-4248
Fax: 617-735-4255
Email: mkontari@bidmc.harvard.edu



Understanding the signaling pathways that mediate cardiac developmental processes may reveal important clues into the cellular and molecular pathogenesis of heart disease. Specifically, we want to understand how protein-tyrosine phosphatases (PTPs) relate to cardiac development and disease. Our lab's research efforts focus on developmental biology, in vivo analysis of in mouse systems, including disease models, and cardiac biology and stem cell research using primary cultures.

Currently, we are studying mouse models in which we can assess the molecular pathogenesis of the congenital cardiac defects associated with Noonan (NS) and LEOPARD (LS) Syndromes, pediatric disorders both attributed primarily to mutations in Shp2. Shp2, encoded by the PTPN11 gene, is a key positive regulator in most, if not all, receptor tyrosine kinase (RTK) signaling pathways, acting upstream of Ras in the Erk/MAP kinase cascade. In this regard, we hope to answer several interesting questions regarding the effects of Shp2 in normal cardiomyocyte development and disease. What is the mechanism by which LS mutations perturb downstream signaling events in the heart, and are other domains in Shp2, such as the tyrosyl phosphorylation sites and the proline-rich stretch, required for the dominant negative effects of the LS mutants? Does deletion of Shp2 have a different effect on cardiomyocyte disease development than the dominant negative (i.e., LS) mutants of Shp2 or does embryonic deletion of Shp2 in the heart have a different phenotype (e.g., HCM) than does post-natal deletion?

In addition, our lab is interested in studying end stage heart failure. Idiopathic dilated cardiomyopathy (IDC) is a disease that results in an enlarged heart that does not pump properly. It is a common reason afflicted individuals require heart transplant surgeries. However, the cause of IDC is unclear and the molecular signaling mechanisms that are aberrantly regulated in IDC are largely unknown. 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). The loss of Shp2 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. 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 study elucidate the mechanisms by which RhoA is regulated by Shp2. This project will examine the role of RhoA activity, via Shp2, in cardioprotection of heart failure. This project addresses several interesting and key questions with regards to the function of RhoA in cardiomyocyte disease development: Is RhoA an important regulator of adult cardiac pathogenesis, i.e., in response to stress and/or injury to the heart? What is/are the receptor tyrosine kinase signaling pathway(s) affected by RhoA activity? What is the RhoGEF, RhoGAP and/or other substrate for Shp2 responsible for the dilated phenotype? Can the failure phenotype be rescued with pharmacological intervention?



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Talita M. Marin, Kimberly Keith, Benjamin Davies, David A. Conner, Prajna Guha, Demetrios Kalaitzidis, Xue Wu , Michael Bauer, Roderick Bronson, Kleber G. Franchini, Benjamin G. Neel and Maria I. Kontaridis. Rapamycin normalizes hypertrophic cardiomyopathy in a mouse model of LEOPARD Syndrome-associated PTPN11 mutation. JCI, 2011 Feb 21. pii: 44972. doi: 10.1172/JCI44972.
Editorial: RAS signaling pathway mutations and hypertrophic cardiomyopathy: getting into and out of the thick of it, Gelb, B, Tartaglia M., J Clin Invest. 2011;121(3):844-847. doi:10.1172/JCI46399.

Stewart RA, Sanda T, Widlund HR, Zhu S, Swanson KD, Hurley AD, Bentires-Alj M, Fisher DE, Kontaridis MI, Look AT, Neel BG. Phosphatase-Dependent and -Independent Functions of Shp2 in Neural Crest Cells Underlie LEOPARD Syndrome Pathogenesis. Dev Cell. 2010 May 18;18(5):750-762.

Kontaridis MI, Yang W, Bence KK, Cullen D, Wang B, Bodyak N, Ke Q, Hinek A, Kang PM, Liao R, Neel BG. 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. 2008;117(11):1423-35.
Editorial: Shp Shape - FAKs about hypertrophy, Martin, KA, Hwa, J., Circ Res. 2008 October 10; 103(8): 776-778

Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006;281(10):6785-92.



© 2013 by the President and Fellows of Harvard College