Pendurthi’ s primary research interest is in the field of hemostasis and thrombosis, particularly in areas related to initiation and regulation of tissue factor-dependent blood coagulation and clotting proteases-induced cell signaling. She is also interested in understanding the role of clotting proteases and cellular receptors in pathogenesis of various diseases, including cancer, inflammation, pulmonary and cardiovascular diseases. Pendurthi did her post-doctoral training in the School of Medicine and the Cancer Center at the University of California San Diego and worked on identifying molecular defects in factor IX in hemophilia patients and investigated cytochrome p450 gene regulation. After coming to UT Health Science Center, she continued her research in hemostasis and thrombosis field, both independently and collaboratively. She had been the P.I. on NIH, AHA and other extramural funded
grants. She has published more than 100 peer-reviewed publications and trained several post-doctoral fellows.
The focus of Pendurthi laboratory is to understand the molecular pathways that control blood coagulation and how the proteins involved in the blood clotting play a role in pathogenesis of various diseases, particularly in cancer and inflammation. Our laboratory basically focuses on two proteins, tissue factor (TF) and endothelial cell protein C receptor (EPCR).
Role of tissue factor in hemostasis and thrombosis: Tissue factor is a transmembrane protein and the primary cellular initiator of the blood clotting cascade. Normally, TF is expressed in perivascular/extravascular cells and not in blood cells or the cells that come in contact with blood. However, specific disease conditions may induce TF expression in these cells. Upon vascular injury, TF is exposed to the blood, and the clotting protease factor VIIa (FVIIa) binds TF. TF-FVIIa complex triggers the coagulation cascade by activating factor IX to factor IXa and factor X to factor Xa. The subsequent reactions generate thrombin, ultimately leading to platelet plug formation and the fibrin assembly that seals the injured site. TF-dependent blood coagulation plays a primary role in hemostasis upon tissue injury, but an aberrant expression of TF leads to thrombotic disorders. Hence, the proper regulation of TF expression is critical not only for maintenance of the hemostatic balance, but also health in general. Therefore, the expression of TF activity on cell surfaces is tightly regulated. A part of our research focuses on understanding cellular mechanisms that regulate TF activity on cell surfaces independent of de novo transcription of the protein. Our studies show that the composition of membrane phospholipids on the cell surface and the cholesterol content in the cell membrane influences the coagulant activity of TF. Our research focuses on understanding how these cell components regulate TF activity on cell surfaces and their relevance to hemostasis and thrombotic disorders.
Endothelial cell protein C receptor and the crosstalk between the coagulation and anticoagulation pathways: Endothelial cell protein C receptor (EPCR) is a cellular receptor for protein C and activated protein C (APC). It is primarily localized on the endothelial cells of large blood vessels. EPCR plays a crucial role in the protein C anticoagulant pathway by promoting the activation of protein C by thrombin-thrombomodulin complex. In the last decade, EPCR has received wide attention as it had been discovered that EPCR also plays a key role in mediating APC-induced cytoprotective effects, including anti-apoptotic, anti-inflammatory, and barrier stabilization. Recent studies indicate that EPCR plays a critical role in the pathogenesis of severe malaria by acting as a receptor for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Studies from our laboratory and others have shown that FVIIa, a clotting protease that binds to TF and initiates the activation of the coagulation cascade, also binds EPCR. FVIIa bound to EPCR on endothelial cells is shown to activate PAR1-mediated cell signaling and provide barrier protective effect. Current studies in the laboratory are focused on understanding how FVIIa interaction with EPCR influences protein C/APC anticoagulant pathway in hemostasis and in rFVIIa therapy of hemophilia patients and patients with other bleeding disorders. Our laboratory is also interested in investigating mechanisms of EPCR-FVIIa-mediated barrier protective effect and exploring its usefulness in treating various diseases where tissue edema is the major problem.
Role of TF and EPCR in cancer and inflammation: Both TF and EPCR, whose primary function is to regulate clotting, also affect various pathophysiological processes, including inflammation and cancer. Studies from our laboratory show that both TF and EPCR may support FVIIa activation of Gprotein coupled protease-activated receptors. Understanding of how TF-FVIIa- and EPCR-FVIIa-induced cell signaling pathways alter cellular functions and influence pathogenesis of cancer and inflammation is one of the focuses of our research. We use breast cancer and malignant pleural mesothelioma (MPM) cell lines and animal model systems in our studies. Our recent studies show that the introduction of EPCR expression to tumor cells through genetic engineering suppressed TF-driven tumor growth in MPM. EPCR-mediated protective effect in cancer appears to be specific to MPM. Our laboratory is interested in identifying the molecular mechanisms by which EPCR suppresses tumor growth of MPM and evaluating the therapeutic potential of EPCR-mediated pathway in curtailing tumor growth.
Research Collaborations: Our laboratory actively collaborates with other investigators within the institute as well as outside investigators. We have a long and ongoing collaboration with Rao laboratory on the role of TF and EPCR in hemostasis and thrombosis and cell signaling. Studies related to malignant pleural mesothelioma and lung diseases are conducted in collaboration with Idell and Tucker laboratories.
Mesothelioma Applied Research Foundation
American Heart Association
National Institute of Health
Research Assistant/Ph.D. student