Kontaridis Lab

Areas of Investigation

My research focuses on understanding the molecular signaling pathways that lead to aberrant regulation of embryonic development and mediate onset of adult disease. In particular, we study the role of protein tyrosine phosphatases and small GTPases in heart development and disease. We have published seminal papers in this field and have garnered a number of extramural grants, both from foundations, industry and NIH. We have also generated a number of tools and techniques including generation of novel in vivo mouse modeling systems and cutting-edge molecular biology techniques, to help conduct the work proposed herein. In this R01, we propose to investigate the direct functional role(s) of RhoA in mediating fibrosis in response to cardiac stress and injury. Using a combined, comprehensive set of biochemical, proteomic and genetic approaches, this proposal will help us understand the functional significance and mechanisms by which RhoA can regulate fibrotic events that lead to heart disease and failure. In addition, through use of novel nanoparticle technology, we will utilize cell specific delivery of inhibitors to the downstream RhoA effectors, MRTF and SRF, in an effort to bypass upstream protective effects of RhoA, while at the same time, directly targeting deleterious signals that drive myofibroblast activation and fibrosis.

Lab Focus

My lab is interested in investigating the cardio myogenic defects associated with NS and LS, two autosomal dominant congenital RASopathy disorders principally caused by unique mutations in the protein tyrosine phosphatase SHP2. Our lab was the first to generate a mammalian mouse model system to study LS. Consequently, we identified that LS mutations lead to increased AKT/mTOR activity. Moreover, we identified that the cardiac hypertrophy associated with LS could be reversed with treatment of Rapamycin. We are currently in process of moving these studies into multi-site clinical trials, with support from the NIH/NCATS TRND mechanism. In addition, our lab is currently investigating how NS and LS mutations differentially affect cardiac-specific tissue lineages during cardiac development in mouse embryos and in iPSCs.

Efforts in the lab utilize a myriad of tools and techniques including iPS cells, in vivo mouse model systems, and molecular biology techniques. Together, these provide valuable mechanistic and functional information in understanding the differential signaling pathways that cause disease and allow for an individualized approach to therapeutic targeting. Specifically, the lab is focused on four main interests: 

1) Understanding the functional mechanisms associated with SHP2 activity in the development of Systemic Lupus Erythematosus (SLE). The lab is interested in understanding how SHP2 is involved in mediating the onset/propagation of SLE. The lab’s data indicate that SHP2 activity is increased in SLE and that this mediates proliferation of cytotoxic T cells, thereby causing lupus pathogenicity. Use of a novel inhibitor for SHP2 ameliorated SLE pathogenesis; increased lifespan, decreased fibrosis and inflammation in tissues, and reduced the number of skin lesions in SLE-prone mice. These data suggest that development of an SHP2 inhibitor may serve as a novel treatment for SLE.

2) Elucidation of the cardio myogenic defects associated with Noonan (NS) and LEOPARD (LS) Syndromes. The lab is interested in investigating the cardio myogenic defects associated with NS and LS, two autosomal dominant congenital RASopathy disorders principally caused by unique mutations in the protein tyrosine phosphatase SHP2. The Kontaridis group was the first to generate a mammalian mouse model system to study LS. Consequently, they identified that LS mutations led to increased AKT/mTOR activity. Moreover, they identified that the cardiac hypertrophy associated with LS could be reversed with treatment of Rapamycin. The lab is currently in process of moving these studies into multi-site clinical trials, with support from the NIH/NCATS TRND mechanism. In addition, the lab is investigating how NS and LS mutations differentially affect cardiac-specific tissue lineages during cardiac development in mouse embryos and in iPSCs.

3) Determining the phosphatase-independent functions of SHP2 in development and disease. The Kontaridis lab identified novel functional roles for SHP2 in the regulation of downstream signaling events. They were the first to identify that LS-associated SHP2 mutations, unlike the NS mutations, were loss-of-function for phosphatase activity and behaved as dominant-negatives in downstream signaling. This created a paradigm shift that altered the way phosphatases were thought to function in cellular signaling, in general, and suggested that RASopathy disorders should be distinguished by mutational analysis rather than by clinical presentation alone. Currently, the lab is investigating whether SHP2 has unique phosphatase-independent functions critical for the propagation of downstream signaling.

4) Deciphering the cardio protective effects of the small G protein RhoA in the failing adult heart. The Kontaridis lab has discovered that RhoA, an enzyme regulated in part by SHP2, is involved in transitioning compensatory cardiac hypertrophy to heart failure. Moreover, it is involved in fibrosis, making RhoA and its downstream effectors attractive targets for therapeutic approaches in treating cardiac disease. Projects in the lab are focused on elucidating the RhoA-mediated signaling pathways involved in fibrosis and in onset of end-stage heart failure.

Director of Research, Masonic Medical Research Institute

Other Professional Titles : Associate Professor of Medicine, Part-time Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts  

Email: mkontaridis@mmri.edu ,Phone (315) 624-7490, Fax (315) 315-735-5648

Dr. Maria Irene Kontaridis is currently the Director of Research at the Masonic Medical Research Institute in Utica, NY. She also holds a part-time faculty appointment as an Associate Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, Department of Medicine/Division of Cardiology in Boston, MA. Dr. Kontaridis received her undergraduate degrees (B.A. and B.S.) from the University of Florida in Classics and Chemistry, and subsequently, obtained her master’s degrees both in Pharmacology and in Biomedical and Biological Sciences from Yale University in 1999 and 2001, respectively. In 2002, she was awarded a Ph.D. from Yale University for work with Dr. Anton Bennett on the role of protein tyrosine phosphatases, especially SHP2, in cell growth and skeletal muscle differentiation. Dr. Kontaridis' interest in continuing to work on SHP2 phosphatase led her to accept a postdoctoral position with Dr. Benjamin Neel, at Beth Israel Deaconess Medical Center (BIDMC) in 2003. Her work as a postdoctoral fellow garnered extramural support from the American Heart Association and the NIH Pathway to Independence Award (K99/R00).  In 2007, Dr. Kontaridis was promoted to Instructor, and in 2008, was recruited to the Department of Medicine, Division of Cardiology at BIDMC as an Assistant Professor of Medicine at Harvard Medical School. In 2015, she was named the Director of Basic Cardiovascular Research at BIDMC and in 2016 was promoted to Associate Professor of Medicine at Harvard Medical School.  In 2018, Dr. Kontaridis took on a new role as the Director of Research at the Masonic Medical Research Institute in upstate NY. Dr. Kontaridis’ independent research program focuses on the fundamental mechanisms underlying both congenital heart disease and end-stage heart failure, and the processes that lead to abnormal development, aberrant signaling and disease onset. She has made several seminal observations about SHP2 and its role in cardiac pathophysiology and disease, as well as in autoimmunity. Her work has been awarded grants from the Milton Foundation, the Children’s Cardiomyopathy Foundation, the Saving Tiny Hearts Foundation, the Harvard Stem Cell Institute, the Alliance of Lupus Research and the National Institutes of Health (NHLBI-R01s and NCATS-TRND) as well as has garnered support from industry and pharmaceutical companies (Novartis, GSK, Arqule).

Dr. Kontaridis is also actively involved in the medical and research community and has established herself in a number of significant leadership roles. In Boston, she served as co-chair for the Joint Committee on the Status of Women at Harvard Medical School, an important group dedicated to the development and leadership of women in the Harvard community. In addition, she also served as Chair of the Research Safety Committee at BIDMC, dedicated to development of proper work ethics and safety policies for research scientists. Dr. Kontaridis continues to be a member of the Harvard Medical School Biomedical and Biological Sciences Faculty Program, where she has a joint appointment in the department of Biological Chemistry and Molecular Pharmacology and with the Leder Human Biology and Translational Medicine Program of Harvard Medical School. More nationally, Dr. Kontaridis is an appointed Fellow of the American Heart Association, where she has served as chair of the Early Career Committee for the BCVS Council and now serves on the Council of Operations as the Chair of all AHA Early Career Councils. In 2018, Dr. Kontaridis was elected to serve as a Council member for the ISHR-North American Section. She has also co-chaired and organized the Weinstein Conference for Developmental Cardiology in 2015 and the AHA BCVS Summer Conference in 2016. In 2018, she co-chaired the first ever Olympiad in Cardiovascular Medicine Symposium in Athens, Greece.

 

Education

  • 1995 B.S., (Cum Laude), Chemistry, University of Florida
  • 1995 B.A., (Summa Cum Laude), Classical Studies, University of Florida
  • 2000 M.S., Pharmacology and Molecular Medicine, Yale University
  • 2001 M.Phil., Pharmacology and Molecular Medicine, Yale University
  • 2002 Ph.D., Biological and Biomedical Sciences (mentor:  Anton Bennett, Ph.D.), Yale University

 

Postdoctoral Training

  • 2002-2003 Postdoctoral Fellow, Pharmacology (mentor:  Anton Bennett, Ph.D.), Yale University
  • 2003-2007 Research Fellow, Hematology/Oncology (mentor:  Benjamin G. Neel, M.D., Ph.D.), Beth Israel Deaconess Medical Center

Instructor

  • Adife Gulhan Ercan-Sencicek

Postdoctoral Fellows

  • Bing Xu
  • Saravanakkumar Chennappan

Research Associates

  • Mayurika Desai

Research Assistant

  • Yan Sun