The goals of this Midcareer Investigator Award in Patient-Oriented Research are to enhance the ability of Dr. Christie to train, mentor and support the career development of physician scientists pursuing patient oriented research in pulmonary and critical care medicine. These goals will be accomplished through sustained reduction in Dr. Christie's clinical and administrative responsibilities with a resultant increase in effort spent directly on mentoring activities, expanding Dr. Christie's research program to include longer-term outcomes, and acquisition of new research and mentoring skills. Dr. Christie's successful research program investigating acute lung injury following lung transplantation (termed primary graft dysfunction, PGD) will be expanded to provide trainees with an intensive research experience complemented by career development activities specific to each trainee including didactic coursework in degree programs, research seminars, grant writing workshops, and training in responsible conduct of research. The proposed K24 research will address the hypothesis that PGD can be predicted using molecular markers of epithelial injury and TH17 response pre- operatively, and that these molecular mechanisms of lung injury in PGD are linked to subsequent bronchiolitis obliterans syndrome (BOS) risk. PGD is severe acute lung injury occurring in the days after lung transplantation and has a major impact on early morbidity, mortality, and cost. Furthermore, recent studies have linked PGD to increased incidence of BOS, the clinical form of lung allograft dysfunction and the major source of long-term morbidity and mortality in lung transplantation. A leading hypothesis for the observed link of PGD and BOS is that early epithelial injury to the allograft with aberrant repair and recovery leads to persistent injury, inflammation and BOS.
Under Aim 1 we will determine and validate the predictive utility of circulating protein biomarkers of epithelial injury and TH17 response for PGD when measured pre-operatively in lung transplant recipients.
Under Aim 2 we will determine the association of circulating protein biomarkers of epithelial injury and TH17 response measured in the early post-operative period with subsequent development of Bronchiolitis Obliterans Syndrome (BOS). Fulfillment of our aims will expand Dr. Christie's research platform to include BOS and other long-term outcomes, and provide a research platform for trainees to test novel therapies for PGD prevention, and define mechanisms of the link between PGD and longer-term transplant outcomes.

Public Health Relevance

Lung transplantation is a life-saving therapy for many people with advanced lung diseases. Primary graft dysfunction (PGD) is a form of acute lung injury occurring in the days after the transplant that causes the highest early mortality and is associated with an increased risk of long-term rejection of the lung, termed bronchiolitis obliterans syndrome (BOS). Through this Mid-Career Mentoring Award in Patient Oriented Research, the applicant will perform research and train junior physician-researchers to better predict PGD before the operation, and to understand the mechanisms for the link between PGD and later BOS. This project may lead to new targeted treatments to prevent PGD and/or BOS that may increase the life span of lung transplant recipients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Special Emphasis Panel (ZHL1-CSR-X (M1))
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Colombini-Hatch, Sandra
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University of Pennsylvania
Biostatistics & Other Math Sci
Schools of Medicine
United States
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