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Maria Irene Kontaridis, PH.D.

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Biography
1994 - 1995
Rayburn Scholar in Medicine
1995 - 1996
Cantonis Medal of Excellence
2001 - 2001
Graduate Student Travel Award: American Society for Pharmacology and Experimental Therapeutics,
2002 - 2002
Best Presentation/Poster Award: FASEB Phosphatase Meeting, Snowmass, CO
2005 - 2005
Finalist for the Charles A. King Trust Medical Foundation Postdoctoral Fellowship
2005 - 2006
American Heart Association Postdoctoral Fellowship
2006 - 2011
NIH Pathway to Independence (PI) Award (K99/R00)
2010 - 2010
Milton Fund Scholar
2010 - 2010
AHA Best Basic Cardiovascular Sciences Abstract, Scientific Sessions 2010, Chicago, IL, November 16,
2010 - 2012
Session Chair: Protein Phosphatases in Disease and Development
2010
Elected Fellow of the American Heart Association
2010 - 2015
NIH/NHLBI R01
2011
Early Independent Career Research Competition Winner, Keystone Symposia, Cardivascular Disease
2013
Children's Cardiomyopathy Foundation Grant
2013 - 2015
Harvard Stem Cell Institute Seed Grant
2013
Nominated for Outstanding Junior Investigator Award
2013
Finalist for Mentor of the Year Award
2013
Therapeutics for Rare and Neglected Diseases Grant
2013 - 2017
NIH/NHLBI R01

Overview
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.

Research
The research activities and funding listed below are automatically derived from NIH ExPORTER and other sources, which might result in incorrect or missing items. Faculty can login to make corrections and additions.
  1. R01HL114775 (KONTARIDIS, MARIA IRENE) Jun 1, 2013 - Mar 31, 2017
    NIH/NHLBI
    Elucidating the Phosphatase-Independent Roles of PTPN11 in the Heart
    Role: Principal Investigator
  2. R01HL102368 (KONTARIDIS, MARIA IRENE) Apr 15, 2010 - Dec 31, 2021
    NIH/NHLBI
    Role of RhoA in the Molecular Pathogenesis of Heart Disease.
    Role: Principal Investigator
  3. R00HL088514 (KONTARIDIS, MARIA IRENE) Jun 1, 2008 - Nov 30, 2011
    NIH/NHLBI
    Molecular Pathogenesis of the Cardiomyogenic Defects in LEOPARD Syndrome
    Role: Principal Investigator
  4. K99HL088514 (KONTARIDIS, MARIA IRENE) Dec 1, 2006 - Nov 30, 2008
    NIH/NHLBI
    Molecular Pathogenesis of the Cardiomyogenic Defects in LEOPARD Syndrome
    Role: Principal Investigator

Bibliographic
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
  1. Li R, Baskfield A, Lin Y, Beers J, Zou J, Liu C, Jaffré F, Roberts AE, Ottinger EA, Kontaridis MI, Zheng W. 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. Stem Cell Res. 2019 Jan; 34:101374. PMID: 30640061.
    Citations:    Fields:    
  2. Zheng H, Yu WM, Waclaw RR, Kontaridis MI, Neel BG, Qu CK. Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner. Sci Signal. 2018 Mar 20; 11(522). PMID: 29559584.
    Citations:    Fields:    
  3. Sun C, Kontaridis MI. Physiology of Cardiac Development: From Genetics to Signaling to Therapeutic Strategies. Curr Opin Physiol. 2018 Feb; 1:123-139. PMID: 29532042.
    Citations:    
  4. Wang J, Chandrasekhar V, Abbadessa G, Yu Y, Schwartz B, Kontaridis MI. In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy. PLoS One. 2017; 12(6):e0178905. PMID: 28582432.
    Citations:    Fields:    Translation:HumansAnimalsCells
  5. 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. DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress. Sci Signal. 2017 02 28; 10(468). PMID: 28246202.
    Citations: 1     Fields:    Translation:HumansAnimalsCells
  6. Tzanavari T, Varela A, Theocharis S, Ninou E, Kapelouzou A, Cokkinos DV, Kontaridis MI, Karalis KP. Metformin protects against infection-induced myocardial dysfunction. Metabolism. 2016 10; 65(10):1447-58. PMID: 27621180.
    Citations: 3     Fields:    Translation:Animals
  7. 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. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines. J Clin Invest. 2016 08 01; 126(8):2989-3005. PMID: 27348588.
    Citations: 4     Fields:    Translation:AnimalsCells
  8. Wang J, Mizui M, Zeng LF, Bronson R, Finnell M, Terhorst C, Kyttaris VC, Tsokos GC, Zhang ZY, Kontaridis MI. Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus. J Clin Invest. 2016 06 01; 126(6):2077-92. PMID: 27183387.
    Citations: 6     Fields:    Translation:HumansAnimalsCells
  9. 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. A Cross-Species Study of PI3K Protein-Protein Interactions Reveals the Direct Interaction of P85 and SHP2. Sci Rep. 2016 Feb 03; 6:20471. PMID: 26839216; PMCID: PMC4738311.
    Citations: 7     Fields:    Translation:HumansAnimalsCells
  10. Korf B, Ahmadian R, Allanson J, Aoki Y, Bakker A, Wright EB, Denger B, Elgersma Y, Gelb BD, Gripp KW, Kerr B, Kontaridis M, Lazaro C, Linardic C, Lozano R, MacRae CA, Messiaen L, Mulero-Navarro S, Neel B, Plotkin S, Rauen KA, Roberts A, Silva AJ, Sittampalam SG, Zhang C, Schoyer L. The third international meeting on genetic disorders in the RAS/MAPK pathway: towards a therapeutic approach. Am J Med Genet A. 2015 Aug; 167A(8):1741-6. PMID: 25900621; PMCID: PMC4515140.
    Citations: 2     Fields:    Translation:HumansCells
  11. Hahn A, Lauriol J, Thul J, Behnke-Hall K, Logeswaran T, Schänzer A, Bögürcü N, Garvalov BK, Zenker M, Gelb BD, von Gerlach S, Kandolf R, Kontaridis MI, Schranz D. Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog. Am J Med Genet A. 2015 Apr; 167A(4):744-51. PMID: 25708222; PMCID: PMC4598061.
    Citations: 4     Fields:    Translation:HumansCells
  12. Lauriol J, Keith K, Jaffré F, Couvillon A, Saci A, Goonasekera SA, McCarthy JR, Kessinger CW, Wang J, Ke Q, Kang PM, Molkentin JD, Carpenter C, Kontaridis MI. RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis. Sci Signal. 2014 Oct 21; 7(348):ra100. PMID: 25336613; PMCID: PMC4300109.
    Citations: 11     Fields:    Translation:AnimalsCells
  13. Lauriol J, Jaffré F, Kontaridis MI. The role of the protein tyrosine phosphatase SHP2 in cardiac development and disease. Semin Cell Dev Biol. 2015 Jan; 37:73-81. PMID: 25256404; PMCID: PMC4339543.
    Citations: 7     Fields:    Translation:HumansAnimalsCells
  14. Paardekooper Overman J, Yi JS, Bonetti M, Soulsby M, Preisinger C, Stokes MP, Hui L, Silva JC, Overvoorde J, Giansanti P, Heck AJ, Kontaridis MI, den Hertog J, Bennett AM. PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice. Mol Cell Biol. 2014 Aug; 34(15):2874-89. PMID: 24865967; PMCID: PMC4135572.
    Citations: 7     Fields:    Translation:HumansAnimalsCells
  15. Kontaridis MI. How to get a K award: it is not just about the science. Circ Res. 2014 Mar 14; 114(6):941-3. PMID: 24625724; PMCID: PMC3988580.
    Citations: 1     Fields:    Translation:Humans
  16. Dolmatova E, Spagnol G, Boassa D, Baum JR, Keith K, Ambrosi C, Kontaridis MI, Sorgen PL, Sosinsky GE, Duffy HS. Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation. Am J Physiol Heart Circ Physiol. 2012 Nov 15; 303(10):H1208-18. PMID: 22982782; PMCID: PMC3517637.
    Citations: 23     Fields:    Translation:AnimalsCells
  17. Lauriol J, Kontaridis MI. PTPN11-associated mutations in the heart: has LEOPARD changed Its RASpots? Trends Cardiovasc Med. 2011 May; 21(4):97-104. PMID: 22681964; PMCID: PMC3372917.
    Citations: 10     Fields:    Translation:HumansAnimalsCells
  18. Marin TM, Keith K, Davies B, Conner DA, Guha P, Kalaitzidis D, Wu X, Lauriol J, Wang B, Bauer M, Bronson R, Franchini KG, Neel BG, Kontaridis MI. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 2011 Mar; 121(3):1026-43. PMID: 21339643; PMCID: PMC3049377.
    Citations: 79     Fields:    Translation:HumansAnimalsCells
  19. 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):750-62. PMID: 20493809; PMCID: PMC3035154.
    Citations: 38     Fields:    Translation:HumansAnimalsCells
  20. Maria I. Kontaridis, Wentian Yang, Kendra Bence, Darragh Cullen, Bo Wang, Natalya Bodyak, Qingen Ke, Aleksander Hinek, Peter Kang, Ronglih Liao and Benjamin G. Neel . 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. 2008 FASEB: Protein Phosphatases, Snowmass, CO. 2008.
  21. 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 Mar 18; 117(11):1423-35. PMID: 18316486; PMCID: PMC2394674.
    Citations: 30     Fields:    Translation:AnimalsCells
  22. Bentires-Alj, M., Kontaridis, M.I., Neel, B.G. . Stops along the RAS pathway in human genetic disease. Nat Med. 2006 Mar;12(3):283-285. 2006; 12(3):283-285.
  23. 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 Mar 10; 281(10):6785-92. PMID: 16377799.
    Citations: 101     Fields:    Translation:HumansCells
  24. Haider UG, Roos TU, Kontaridis MI, Neel BG, Sorescu D, Griendling KK, Vollmar AM, Dirsch VM. Resveratrol inhibits angiotensin II- and epidermal growth factor-mediated Akt activation: role of Gab1 and Shp2. Mol Pharmacol. 2005 Jul; 68(1):41-8. PMID: 15849355.
    Citations: 13     Fields:    Translation:AnimalsCells
  25. Kontaridis MI, Eminaga S, Fornaro M, Zito CI, Sordella R, Settleman J, Bennett AM. SHP-2 positively regulates myogenesis by coupling to the Rho GTPase signaling pathway. Mol Cell Biol. 2004 Jun; 24(12):5340-52. PMID: 15169898; PMCID: PMC419889.
    Citations: 42     Fields:    Translation:AnimalsCells
  26. Ivins Zito C, Kontaridis MI, Fornaro M, Feng GS, Bennett AM. SHP-2 regulates the phosphatidylinositide 3'-kinase/Akt pathway and suppresses caspase 3-mediated apoptosis. J Cell Physiol. 2004 May; 199(2):227-36. PMID: 15040005.
    Citations: 27     Fields:    Translation:AnimalsCells
  27. Zhang SQ, Yang W, Kontaridis MI, Bivona TG, Wen G, Araki T, Luo J, Thompson JA, Schraven BL, Philips MR, Neel BG. Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol Cell. 2004 Feb 13; 13(3):341-55. PMID: 14967142.
    Citations: 139     Fields:    Translation:AnimalsCells
  28. Kontaridis, Maria I. Functional Role of the protein tyrosine phosphatase, Shp2, in skeletal muscle differentiation. 2002.
  29. Kontaridis MI, Liu X, Zhang L, Bennett AM. Role of SHP-2 in fibroblast growth factor receptor-mediated suppression of myogenesis in C2C12 myoblasts. Mol Cell Biol. 2002 Jun; 22(11):3875-91. PMID: 11997521; PMCID: PMC133814.
    Citations: 16     Fields:    Translation:AnimalsCells
  30. Kontaridis MI, Liu X, Zhang L, Bennett AM. SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis. J Cell Sci. 2001 Jun; 114(Pt 11):2187-98. PMID: 11493654.
    Citations: 12     Fields:    Translation:AnimalsCells
  31. Edwards PD, Topping D, Kontaridis MI, Moldawer LL, Copeland EM, Lind DS. Arginine-enhanced enteral nutrition augments the growth of a nitric oxide-producing tumor. JPEN J Parenter Enteral Nutr. 1997 Jul-Aug; 21(4):215-9. PMID: 9252947.
    Citations: 1     Fields:    Translation:AnimalsCells
  32. Lind DS, Kontaridis MI, Edwards PD, Josephs MD, Moldawer LL, Copeland EM. Nitric oxide contributes to adriamycin's antitumor effect. J Surg Res. 1997 May; 69(2):283-7. PMID: 9224394.
    Citations: 3     Fields:    Translation:AnimalsCells
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Funded by the NIH/NCATS Clinical and Translational Science Award (CTSA) program, grant number UL1TR001102, and through institutional support from Harvard University, Harvard Medical School, Harvard T.H. Chan School of Public Health, Beth Israel Deaconess Medical Center, Boston Children's Hospital, Brigham and Women's Hospital, Massachusetts General Hospital and the Dana Farber Cancer Institute.