The research in the laboratory of Sanda Predescu, PhD, is focused on the molecular mechanisms of endothelial cell functions in normal and pathological conditions and how intersectin proteins regulate these functions. Currently, we investigate the involvement of intersectin-1s in endothelial cell hyper-proliferation, abnormal neovascularization and vascular malfunctions, hallmarks of acute respiratory distress syndrome (ARDS), human pulmonary arterial hypertension (PAH) and malignant disorders.
Our work
Currently, our research is focused on three projects:
1. Cleavage of Intersectin-1s by Granzyme B and Pulmonary Arterial Hypertension.
2. Microparticles and paracrine Alk5/TGF beta Receptor I signaling in ARDS
3. Intersectin-1s deficiency and its role in lung cancer tumorigenesis and metastasis.
To define the molecular mechanisms and signaling networks involved we are using a combination of molecular, biochemical and morphological approaches to study a variety of mammalian systems including cells in culture, mouse mutants, mammalian and human tissues.
Our studies demonstrate that mice with targeted disruption of intersectin-1s gene and lung expression of a NH2-terminal protein fragment of intersectin-1s produced by granzyme B proteolytic cleavage during inflammation associated with PAH, develop a PAH phenotype, with severe medial wall hypertrophy and intima proliferation in pulmonary arteries as well as obliterative and complex plexiform-like lesions as seen in PAH patients. Currently we investigate the transcriptional and signaling mechanisms responsible for this severe arteriopathy with the goal of developing novel therapeutic strategies to ameliorate and perhaps, reverse the endothelial cell plexiform phenotype already established in severe human PAH.
We have also shown that the lung tissue of Acute Respiratory Distress Syndrome (ARDS) subjects show decreased intersectin-1s protein expression. Moreover, the blood of ARDS patients comprises a sub-population of circulatory microparticles that contain the TGF receptor 1. Currently, we use translational approaches to characterize morphologically and biochemically these microparticles and define their effect on pulmonary microvascular endothelial cells and possible involvement in repairing the vascular injury and restoring pulmonary function.
Finally, our studies indicated that human lung cancer cells and tissue display significant downregulation of intersectin-1s protein expression; restoring intersectin-1s in lung cancer cells reduced their proliferation and clonogenic potential. Currently, we test the hypothesis that decreased intersectin-1s expression in human lung cancer cells induces reorganization of the cellular cytoskeleton and interferes with the cell cycle, leading to increased cell migration, lung cancer progression and metastasis.
Funding
NIH/NHLBI R01 HL127022
Our team
Dan Predescu, MD
Shanshan Qin, MD
Mona Vashi, MD, Fellow, Pulmonary and Critical Care
Cristina Bardita, MD, PhD, Resident, Internal Medicine
Contact Us
Sanda Predescu, PhD
Phone: (312) 563-2437
Fax: (312) 942-0339
Email: sanda_predescu@rush.edu