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.
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.
|Cantu, Edward; Shah, Rupal J; Lin, Wei et al. (2015) Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation. J Thorac Cardiovasc Surg 149:596-602|
|Wong, Hector R; Lindsell, Christopher J; Pettilä, Ville et al. (2014) A multibiomarker-based outcome risk stratification model for adult septic shock*. Crit Care Med 42:781-9|
|Diamond, Joshua M; Akimova, Tatiana; Kazi, Altaf et al. (2014) Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction. Am J Respir Crit Care Med 189:567-75|
|Shah, Rupal J; Christie, Jason D (2014) Response. Chest 145:193|
|Cohen, David G; Christie, Jason D; Anderson, Brian J et al. (2014) Cognitive function, mental health, and health-related quality of life after lung transplantation. Ann Am Thorac Soc 11:522-30|
|Todd, Jamie L; Christie, Jason D; Palmer, Scott M (2014) Update in lung transplantation 2013. Am J Respir Crit Care Med 190:19-24|
|Chatterjee, Shampa; Nieman, Gary F; Christie, Jason D et al. (2014) Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307:L668-80|
|Reilly, John P; Bellamy, Scarlett; Shashaty, Michael G S et al. (2014) Heterogeneous phenotypes of acute respiratory distress syndrome after major trauma. Ann Am Thorac Soc 11:728-36|
|Baldwin, Matthew R; Reid, M Cary; Westlake, Amanda A et al. (2014) The feasibility of measuring frailty to predict disability and mortality in older medical intensive care unit survivors. J Crit Care 29:401-8|
|Reilly, John P; Meyer, Nuala J; Shashaty, Michael G S et al. (2014) ABO blood type A is associated with increased risk of ARDS in whites following both major trauma and severe sepsis. Chest 145:753-61|
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