Mourad Toporsian, Ph.D.
Instructor in Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-223
Boston, MA 02215
Mourad Toporsian earned a PhD in Experimental Medicine from McGill University, Montreal, Canada (2000) and then pursued postdoctoral studies at the Hospital for Sick Children (University of Toronto) with Michelle Letarte. In 2008, he was recruited to the Division Pulmonary, Critical Care and Sleep Medicine at the Beth Israel Deaconess Medical Center and is a member of the CVBR.
Research Interests: Endothelial mechanisms in pulmonary vascular disease
My lab is interested in elucidating the endothelial mechanisms involved in pulmonary vascular health and disease. In particular, we study the impact of changes in cellular oxygen tension on redox-dependent RNA processing, protein-protein interactions and cellular signal transduction. We frequently use animal models to translate our basic science findings at the molecular level to pulmonary vascular health and disease. We are currently interested in two aspects of pulmonary vascular biology: 1) Pulmonary Arterial Hypertension and 2) Endothelial Oxygen Sensing and Hypoxic Pulmonary Vasoconstriction.
Basic Research - Pulmonary Arterial Hypertension (PAH). PAH is a devastating disorder which can affect individuals of all ages worldwide. It is characterized by a sustained elevation in pulmonary vascular pressure due to pruning or loss of blood vessels and muscularization of the remaining arteries that perfuse the lung. We have isolated novel endothelial targets that may play a role in PAH pathogenesis. One of these proteins, namely endoglin, is an accessory receptor of the transforming growth factor (TGF)-?/bone morphogenetic protein (BMP) signaling pathways and is known to play an essential role in endothelial cell function and survival. We are currently analyzing its effects on endothelial redox signaling with special emphasis on the impact of nitric oxide (NO)-mediated posttranslational processing of key proteins involved in endothelial and vasomotor function.
Endothelial Oxygen Sensing and Hypoxic Pulmonary Vasoconstriction.. The lung harbors endothelial cells that are constantly exposed to extremes in oxygen tension, suggesting the importance endothelial heterogeneity in pulmonary vascular homeostasis. Moreover, in contrast to other organs such as the kidney, pulmonary arteries vasoconstrict in response to low oxygen tension (hypoxia). We are interested in elucidating the cellular and molecular basis of endothelial oxygen sensing and hypoxic pulmonary vasoconstriction, phenomena highly relevant to PAH pathogenesis.Translational Research - In collaboration with Dr. Norbert Voelkel (University of Virginia) and Dr. David Roberts (BIDMC/Harvard Medical School),potential biomarkers that are unraveled in our basic science studies are then tested for in humans afflicted with PAH in order to establish diagnostic tests and suggest new therapeutic interventions.
New and Noteworthy Publications:
Toporsian M., Gros R., Kabir MG, Vera S. Govindaraju K., Eidelman D.H., Husain M. Letarte M. A Role for Endoglin in Coupling eNOS Activity and Regulating Local Vascular Tone Revealed in Hereditary Hemorrhagic Telangiectasia. Circulation Research 96(6):684-92, 2005. This study describes a previously unrecognized role for endoglin to bind the endothelial nitric oxide synthase (eNOS) and regulate its activation state. Reduced eNOS/Endoglin interaction is associated with uncoupling of eNOS activity leading to increased endothelial oxidative stress.
Venkatesha S.*, Toporsian M.*, Lam C., Hanai, J., Mammoto, T.,. Kim, Y.M., Bdolah, Y., Lim KH, Yuan H-T, Libermann T., Stillman I.E., Roberts D., D’Amore P.A., Epstein F.H., Sellke F., Romero R., Sukhatme V.P., Letarte M., Karumanchi S.A. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nature Medicine 2006 Jun;12(6):642-9. *These authors have equally contributed to this work. This study describes a novel soluble form of endoglin (sEng) that is produced by the placenta, secreted into the maternal circulation, and contributes to the pathogenesis of preeclampsia by interfering with TGF-? mediated sensitization of eNOS to activation. This was the first study to link TGF-? signaling to eNOS-mediated vasomotor tone.