University of Virginia Health System

TCV SURGERY RESEARCH AREAS

LUNG TRANSPLANT ISCHEMIA-REPERFUSION INJURY
Although there has been considerable progress in lung transplant biology, post-transplant ischemia-reperfusion (IR) injury remains the major source of early mortality. Our lab is utilizing several animal models of IR injury to study mechanisms of this injury in terms of endothelial cell injury, the role of adenosine and nitric oxide and the role of resident lung leukocytes.

COMPENSATORY LUNG GROWTH
Pneumonectomy (removal of a lung) results in rapid, hyperplastic, compensatory growth of the remaining lung. The molecular mechanisms that regulate this regenerative growth are not well known. An understanding of these mechanisms and the role of angiogenesis and angiogenic growth factors in this growth could lead to therapies for lung injury, pulmonary hypertension, respiratory failure, transplantation for endstage lung disease, and even stimulation of regenerative growth in patients with minimal pulmonary tissues left after lung resection.

AORTIC ANEURYSM FORMATION
Aortic aneurysms comprise the 10th leading cause of death accounting for more than 16,000 deaths yearly. To date, there have been no medical therapies proven to prevent or treat aortic aneurysms. Thus, understanding molecular mechanisms for this disease are critical to developing novel treatment strategies. The majority of laboratories investigating aortic aneurysms have focused on leukocyte infiltration and MMP production, while little is known about the role of smooth muscle cells (SMCs). Early in the course of aneurysm formation, SMCs undergo proliferation; however, in maturing aneurysms, smooth muscle cells (SMCs) undergo apoptosis, thereby eliminating cells that are the primary source for the extracellular matrix. There is significant data to suggest SMCs are plastic and have the ability to undergo phenotypic switching in response to environmental cues. One of our goals is to identify SMC phenotype during aneurysm formation. Of major significance, studies in our lab are determining the role of IL-1β induced changes in SMC gene expression as well as direct assessment of the role of IL-1 signaling in SMC phenotypic switching in vivo during aneurysm formation using a variety of unique transgenic and knockout mice developed in the mentor's laboratory. Further experiments include the use of a conditional KLF4 KO mouse, a downstream effector of IL-1β developed by the mentor to determine the mechanisms by which IL-1β exerts its effects. With expanded knowledge of the regulators of SMC phenotype in aneurysm formation, these experiments may lead to novel therapies to alter SMC phenotype, cease degradation of the aortic wall, and remodel the aortic wall matrix.

CARDIOPULMONARY TRANSPLANTATION & IMMUNOLOGY 
Our laboratory is interested in understanding mechanisms involved in cardiothoracic transplantation rejection. Along this avenue we are focusing on adenosine signaling, both endogenous adensine and use of adenosine agonists as therapeutic treatments, in cardiothoracic transplantation. We use multiple models to investigate our aims including the murine heterotopic and orthotopic tracheal transplant models for chronic lung transplant rejection, the orthotopic heart transplant model, and the left lung hilar clamp model for lung ischemia-reperfusion injury. Another area of research we are actively investigating is mechanisms of lung tumor invasiveness.