Maria Irene Kontaridis

Maria Irene Kontaridis, Ph.D.

Associate Professor of Medicine

I have an active research interest in understanding the fundamental mechanisms underlying the development of the heart and the perturbations in molecular signaling pathways that cause cardiomyopathy and heart failure. Specifically, my lab focuses on the contribution of protein tyrosine phosphatases (PTPs) in cardiac development and disease. Through developmental biology, in vivo analyses in mouse systems, including disease models, tissue culture, cardiac biology and stem cell research, I plan to define the functional significance of protein tyrosine phosphatases (PTPs), particularly the PTP SHP2, in the heart.

The major focus in the lab centers on elucidating the cardiomyogenic defects associated with Noonan and LEOPARD Syndromes, two autosomal dominant congenital disorders primarily caused by unique mutations in Shp2. These models provide valuable mechanistic and functional information in understanding the differential signaling pathways and developmental processes leading to each disease. Our hope is that understanding the regulatory mechanisms of these rare disorders will help elucidate functional targets for perhaps even more common congenital diseases. We are focusing on several major questions: A) What is the basis for the distinct cardiac phenotypes in NS and LS; B) Do NS and LS aberrantly regulate unique cardiovascular developmental pathways; and C) Can we reverse some/all syndrome phenotypes (and how)? To this end, (as part of my work on the K99/R00 on LS), we generated an LS mouse model to provide initial answers to the major questions above, including our most important finding that hypertrophic cardiomyopathy (HCM) in LS can be reversed by rapamycin (because unlike other RASopathy genes, LS mutants primarily cause Akt/mTorc1 activation). These findings argue for a “personalized” approach to RASopathy treatment. Indeed, we have recently received the prestigious TRND grant from the NIH, which will provide us the resources and infrastructure to initiate the necessary multi-site clinical trials needed for treatment of HCM in patients with LS. In addition, our lab has recently been awarded an R01 from the NIH/NHLBI to elucidate the potential mechanisms by which developmental defects in SHP2 contribute to the adult-onset HCM phenotype. In this regard, we also hope to identify the contribution of phosphatase dependent vs. independent mechanisms to these abnormalities and developmental defects.

A second focus of my lab is on understanding the functional role and mechanisms by which Shp2 activity is involved in the development of systemic lupus erythematosus (SLE). We are focusing on several major questions: A) What is the basis for the correlation between SLE and increased SHP2 activity; B) What are the functional mechanisms/signaling pathways associated with SLE onset; and C) Can we reverse some/all SLE syndrome phenotypes with an SHP2 inhibitor?

Finally, we are also interested in elucidating the potential cardioprotective effects of the small GTPase RhoA in the adult heart. Through funding by a second R01 from the NIH/NHLBI, we are interested in determining whether the loss of RhoA adversely affects myocardial homeostasis, whether loss of RhoA expression and/or activity can rescue the cardiac defects associated with Shp2 deletion in vivo and to identify the signaling mechanism(s) by which Shp2 regulates RhoA activity in the myocardium.

Publications View
Inducible Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1-Associated Noonan Syndrome.
Authors: Authors: Jaffré F, Miller CL, Schänzer A, Evans T, Roberts AE, Hahn A, Kontaridis MI.
Circulation
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Generation of an induced pluripotent stem cell line (TRNDi003-A) from a Noonan syndrome with multiple lentigines (NSML) patient carrying a p.Q510P mutation in the PTPN11 gene.
Authors: Authors: Li R, Baskfield A, Lin Y, Beers J, Zou J, Liu C, Jaffré F, Roberts AE, Ottinger EA, Kontaridis MI, Zheng W.
Stem Cell Res
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Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner.
Authors: Authors: Zheng H, Yu WM, Waclaw RR, Kontaridis MI, Neel BG, Qu CK.
Sci Signal
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Physiology of Cardiac Development: From Genetics to Signaling to Therapeutic Strategies.
Authors: Authors: Sun C, Kontaridis MI.
Curr Opin Physiol
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DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress.
Authors: Authors: Simonson B, Subramanya V, Chan MC, Zhang A, Franchino H, Ottaviano F, Mishra MK, Knight AC, Hunt D, Ghiran I, Khurana TS, Kontaridis MI, Rosenzweig A, Das S.
Sci Signal
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In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy.
Authors: Authors: Wang J, Chandrasekhar V, Abbadessa G, Yu Y, Schwartz B, Kontaridis MI.
PLoS One
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Metformin protects against infection-induced myocardial dysfunction.
Authors: Authors: Tzanavari T, Varela A, Theocharis S, Ninou E, Kapelouzou A, Cokkinos DV, Kontaridis MI, Karalis KP.
Metabolism
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Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines.
Authors: Authors: Lauriol J, Cabrera JR, Roy A, Keith K, Hough SM, Damilano F, Wang B, Segarra GC, Flessa ME, Miller LE, Das S, Bronson R, Lee KH, Kontaridis MI.
J Clin Invest
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Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus.
Authors: Authors: Wang J, Mizui M, Zeng LF, Bronson R, Finnell M, Terhorst C, Kyttaris VC, Tsokos GC, Zhang ZY, Kontaridis MI.
J Clin Invest
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A Cross-Species Study of PI3K Protein-Protein Interactions Reveals the Direct Interaction of P85 and SHP2.
Authors: Authors: Breitkopf SB, Yang X, Begley MJ, Kulkarni M, Chiu YH, Turke AB, Lauriol J, Yuan M, Qi J, Engelman JA, Hong P, Kontaridis MI, Cantley LC, Perrimon N, Asara JM.
Sci Rep
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