The candidate plans a career as a clinical epidemiologist focusing on translational research, bridging basic science and clinical pulmonary medicine. Training will include formal epidemiological course work toward a Master's degree, a mentored laboratory experience, and closely mentored completion of the research protocol. The University of Pennsylvania is a uniquely suited environment for this training award. The Center for Clinical Epidemiology and Biostatistics will provide formal coursework and structured mentoring. The clinical and laboratory Cores of the NHLBI Acute Lung Injury SCOR grant will provide research support. Primary graft failure (PGF) is a devastating acute lung injury syndrome following lung transplantation, which complicates up to 35 percent of all lung transplants. The predominant mechanism underlying this response is currently felt to be ischemia-reperfusion injury. PGF has a profound impact on outcomes following lung transplantation, markedly increasing length of hospitalization, length of time requiring mechanical ventilation, mortality and overall cost. Despite the clear importance of PGF, little is known of the donor and recipient risk factors or pathophysiologic mechanisms contributing to this devastating syndrome. This protocol describes an investigation of the clinical and biologic risk factors for development of primary graft failure. As well, the protocol aims to shed light on the basic mechanisms of PGF by focusing on the role of oxidant stress. The study has three specific aims: (1) to examine the relationship between clinical parameters and the incidence of PGF; (2) to test the hypothesis that elevated plasma levels of selected biomarkers of oxidant stress in the lung transplant donor and recipient are preoperative risk factors for the development of PGF; (3) to test the hypothesis that elevated postoperative levels of selected biomarkers of oxidant stress coincide with development of PGF. Clinical risk factors will be evaluated by carrying out a retrospective cohort study of all lung transplants at the University of Pennsylvania Medical Center. Analysis will include univariate and multivariable explanatory models, and a clinical prediction rule will be developed. Biomarkers will be evaluated as risk factors and as coinciding with the development of PGF by carrying out a prospective cohort study. This protocol will provide new insights into the clinical risk factors for the development of PGF, will evaluate biomarkers of oxidant stress for its early detection, and may provide a mechanistic basis for new approaches to specific therapy.
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