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The overall goal of my fledgling laboratory is to understand the pathobiology which causes vascular remodeling in severe human pulmonary hypertension. Severe pulmonary hypertension (PH) occurs in idiopathic form and is also observed in diseases as diverse as chronic venous thromboembolism, scleroderma, HIV infection, and cirrhosis. In advanced human disease of many etiologies, endothelial proliferation and medial hypertrophy ultimately obliterate the lumen.
Our main experimental approach to the study of PH is a rat model that recapitulates the histopathology, severe hemodynamic alterations, and right ventricular heart failure seen in advanced human disease. This rat model employs right pneumonectomy (a high flow state) with endothelial injury (monocrotaline) to cause lethal pulmonary hypertension in about 4 weeks. We study exercise tolerance on a treadmill as the animals develop disease. At the time of sacrifice, we perform heart catheterizations on anesthetized animals and then do detailed histology studies on fixed tissue. Ultimately, we will be studying serum mediators and tissue gene expression. More basic experiments with smooth muscle and endothelial cell cultures are helping us to understand how altered cellular growth and migration play a role in the vascular pathology of PH.
Currently, there are two molecules of interest in the laboratory, tissue factor and endothelin-1. Tissue factor (TF) is a transmembrane glycoprotein that initiates the coagulation cascade and may also participate in angiogenesis; its regulation is responsive to inflammation and mechanical forces. Despite the known occurrence of in situ thrombosis and several reports linking platelet activation to the etiology of severe disease, TF has not been studied in PH. TF is not present in the normal media; it is abnormally expressed in both the vascular smooth muscle and the endothelium of pulmonary arterioles in patients with severe PH. We are also testing the hypothesis that tissue factor (TF) expression is essential in the initiation and/or propagation of the endothelial and smooth muscle remodeling.
Endothelin-1 (ET) is a major focus of a number of laboratories studying pulmonary hypertension, and we are doing detailed studies on ET biology as it relates to smooth muscle and endothelial cells in culture. We are also exploring the changes in ET receptor profile in our animal model. Since ET antagonists are mainstay of therapy for human PH, these studies have immediate clinical relevance.
Mark Taubman is the sponsor for my pending K08 award and my scientific mentor. The lab has one MD/PhD student and a technician. I am currently interested in recruiting an energetic post-doctoral fellow.
Advancing our understanding of the basic mechanisms responsible for normal and pathological function of the cardiovascular system.
