R. James White, M.D., Ph.D.
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R. James White, M.D., Ph.D.
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Research
- Modeling Severe Pulmonary Hypertension Using Monocrotaline and Pneumonectomy in Rats
- Regulation of Tissue Factor Expression In Vascular Cells Derived from the Pulmonary Circulation
- Endothelin Mediated Signaling in Pulmonary Vascular Cells
Background
Working with my colleagues in pulmonary medicine and cardiology, I am currently building a clinical and basic science program studying pulmonary hypertension. My past includes an undergraduate education at Ohio State University and combined degree training at the University of Pittsburgh. I am the proud protege of a neuropharamacologist named Ian Reynolds (still at Pitt). I moved to Rochester to complete training in Internal Medicine, Pulmonary Diseases, and Critical Care. Now, Mark Taubman is mentoring my scientific career here at the U of R as I begin a career in vascular biology. I have an outpatient clinic in which I am exclusively seeing patients with pulmonary hypertension due to pulmonary emboli, scleroderma, liver cirrhosis, and idiopathic (primary) disease. I spend most of my time as a basic scientist but still enjoy the truly gratifying work of patient care as faculty in the intensive care setting.
Research Overview
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.
Recent Publications
- White, R.J. (2004) A “Radical” Idea Comes of Age: Mitochondrial Oxidant Signaling in Health and Disease. Journal of Molecular and Cellular Cardiology, 37(6): 1115-1117. (Invited Editorial)
- White, R.J. (2004) Pulmonary Arterial Hypertension: Building a Better Mouse Trap for 2010. Drug Discovery Today: Therapeutic Strategies. 1(3): 351-359. (Invited Review)