Maria Kontaridis
Associate Professor of Medicine at Harvard Medical School
Schools
- Harvard Medical School
Links
Biography
Harvard Medical School
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.
Videos
Dr. Maria Kontaridis give an overview of her Lupus (SLE) Research
Maria Kontaridis Vaccination Message
Dr Maria Kontaridis
Masonic Medical Research Institute - Dr. Maria Kontaridis
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