My focus is to understand the vascular biology of pulmonary arterial hypertension (PAH) and to apply the best science in the care of patients.  The lab uses a rat model of severe PAH (pneumonectomy and monocrotaline) and we measure the effects of PAH on exercise tolerance, hemodynamics, and angiography.   We are testing novel small molecules that might be useful in treating patients with this devastating disease. On the clinical side, I am currently treating ~130 patients for PAH with 30 patients on Remodulin or Flolan. Our outpatient group is actively enrolling in national clinical trials and a registry for PAH.

Biography

My sordid past includes an undergraduate education at Ohio State University and combined degree training at the University of Pittsburgh. I am the proud protégé of a neuropharamacologist named Ian Reynolds (now at Merck).  The over-riding goal of my PhD work was to understand how alterations in calcium buffering might lead to increased neuronal vulnerability following agonist-mediated insults. Specifically, I investigated mitochondria and the role that they play in the ability of cultured forebrain neurons to buffer agonist-induced calcium loads.  The follow-up study defined fluorescence imaging techniques for the real time measurement of mitochondrial membrane potential in cultured neurons using JC-1 and demonstrated that agonist-induced accumulation of mitochondrial Ca2+ stores results in mitochondrial depolarization.  

Mark Taubman is my scientific mentor here at the U of R as I develop a career in vascular biology.  Since mitochondria probably play a key role in matching alveolar ventilation with lung perfusion (V/Q matching), the study of pulmonary vascular disease dovetails my long standing interest in mitochondrial function with my current interest in clinical pulmonary hypertension.

Mary Parkes: The Regional Referral Center for Pulmonary Hypertension

I direct the program in pulmonary hypertension, and we exclusively follow patients with pulmonary arterial hypertension: idiopathic disease and that associated with congenital heart disease, scleroderma, liver cirrhosis, and anorexigens.  Of course, we also see a large number of patients with echocardiogram identified PH who do not have PAH, and thus we train fellows in the important distinction between WHO Group 1 PAH and all other forms of pulmonary hypertension.   We also work in close association with physicians at the UC San Diego providing timely evaluation and referral for patients with chronic pulmonary emboli who might be candidates for thromboendarterectomy.  Our operation is ably managed by Karen Frutiger, RN, who enrolls patients in clinical trials and provides triage assistance for the day-to-day care of all of our patients.  We were a top enrolling site for the now complete oral tadalafil trial (PHIRST); we were one of the first sites enrolling patients in oral Remodulin (FREEDOM), and we are actively participating in the REVEAL Registry.  Jake Lyons, a senior pulmonary fellow, is a named co-investigator on all of our clinical trial work, and fellows have an opportunity to spend time learning about PAH.  We are also doing industry sponsored, investigator-initiated clinical trial work studying a novel use of iloprost in the postoperative setting.

We follow a diverse patient population from all over the New York area including northern Pennsylvania.  Some of our patients have been on treatment since 1995, and our patients are very supportive of one another through formal and informal channels.  We follow almost 30 patients on subcutaneous Remodulin, one patient on intravenous Flolan, and approximately 100 other patients on oral therapy or in clinical trials.  We have successfully transitioned many patients from intravenous Flolan to subcutaneous Remodulin; in almost every case, they enjoy a much better lifestyle after the switch.

I spend most of my time on PAH but still enjoy the gratifying work of patient care as faculty in the intensive care setting.  Working with our terrific housestaff and fellows is part of the pleasure.

What's going on in the lab?

The overall goal of my laboratory is to understand the vascular biology which causes severe human pulmonary arterial hypertension.  In advanced human disease of many etiologies, endothelial proliferation and medial hypertrophy ultimately obliterate the lumen. 

Our main experimental approach to the study of PAH 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 left pneumonectomy (promotes contralateral lung growth) 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 and angiography on anesthetized animals and then do detailed histology studies on fixed tissue.  We hypothesize that tissue factor (the membrane bound glycoprotein which initiates coagulation) is an important contributor to disease progression. Despite the known occurrence of in situ thrombosis and several reports linking platelet activation to the etiology of severe disease, TF had not been studied in PAH.   TF is not present in the normal vessel media; it is abnormally expressed in both the vascular smooth muscle and the endothelium of pulmonary arterioles in human patients and rats with severe PAH.  We are actively testing small molecule inhibitors as novel therapies in this devastating disease.

A second line of investigation seeks to define the role of thrombin and the PAR1 receptor in PAH.  In endothelial cells isolated from the rat pulmonary microvasculature, PAR1 activation promotes migration, wound closure, and tube formation in in vitro angiogenesis assays.  The migratory activity is dependent on the matrix (fibronectin or collagen) and the microvascular endothelial cells behave differently than those derived from the proximal pulmonary artery.  We hypothesize that plexiform lesions result from exuberant proliferation after these cells migrate to sites of injury rich in a fibronectin matrix.  This is the work of the M.D. Ph.D. student in my laboratory, David Meoli.

The lab employs David and a technician, Bob Swarthout.  I am currently interested in recruiting an energetic post-doctoral fellow..

Publications

White, R.J., Galaria, I.I., Harvey, J., Blaxall, B.C., Cool, C.D., Taubman, M.B. (2005) Tissue Factor Is Induced In A Rodent Model Of Severe Pulmonary Hypertension Characterized By Neointimal Lesions Typical Of Human Disease, Chest, 128:612S-613S.  [Procs Aspen Lung Conference, 2004]

White, R.J., Meoli, D.F., Kallop, D.Y., Galaria, I.I., Harvey, J.L., Miller, C.M., Massett, M.P., Blaxall, B.C., Hall, C.M., Pierce, R.A., Cool, C.D., Taubman, M.B. (2006) Plexiform-Like Lesions and Increased Tissue Factor Expression in a Rat Model of Severe Pulmonary Hypertension, Am J Phys: Lung Cell Mol Phys, In Revision

Gough, M.S. and White, R.J. (2007) Sildenafil Improves Hemodynamics in Liver Transplantation Candidates with Pulmonary Hypertension, In preparation for Am J Resp Crit Care Med.

Meoli, D.F., Taubman, M.B., White, R. J. (2007) Thrombin induces pulmonary microvascular endothelial cell migration: dependence on fibronectin and CAM Kinase II, In preparation for Circ Res.

Editorials and Invited Reviews

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. In Press. (Invited Review)