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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
1K24HL115354-01
Application #
8366870
Study Section
Special Emphasis Panel (ZHL1-CSR-X (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2012-08-03
Project End
2017-07-31
Budget Start
2012-08-03
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$117,948
Indirect Cost
$8,737
Name
University of Pennsylvania
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Anderson, Brian J; Reilly, John P; Shashaty, Michael G S et al. (2016) Admission plasma levels of the neuronal injury marker neuron-specific enolase are associated with mortality and delirium in sepsis. J Crit Care 36:18-23
Reilly, John P; Anderson, Brian J; Hudock, Kristin M et al. (2016) Neutropenic sepsis is associated with distinct clinical and biological characteristics: a cohort study of severe sepsis. Crit Care 20:222
Palakshappa, Jessica A; Anderson, Brian J; Reilly, John P et al. (2016) Low Plasma Levels of Adiponectin Do Not Explain Acute Respiratory Distress Syndrome Risk: a Prospective Cohort Study of Patients with Severe Sepsis. Crit Care 20:71
Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure et al. (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656-65
Diamond, J M; Shah, R J; Cantu 3rd, E et al. (2016) Survey of Lung Transplant Community's Views on Primary Graft Dysfunction. Am J Transplant 16:724-6
Diamond, Joshua M; Porteous, Mary K; Jackson Roberts 2nd, L et al. (2016) The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia. J Heart Lung Transplant 35:500-7
Cantu, E; Suzuki, Y; Diamond, J M et al. (2016) Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk. Am J Transplant 16:833-40
Shashaty, Michael G S; Reilly, John P; Sims, Carrie A et al. (2016) Plasma Levels of Receptor Interacting Protein Kinase-3 (RIP3), an Essential Mediator of Necroptosis, are Associated with Acute Kidney Injury in Critically Ill Trauma Patients. Shock 46:139-43
Palakshappa, Jessica A; Christie, Jason D (2016) Survivorship Research: Studying the Past to Define the Future. Crit Care Med 44:1422-3
Eberlein, Michael; Reed, Robert M; Bolukbas, Servet et al. (2015) Lung size mismatch and primary graft dysfunction after bilateral lung transplantation. J Heart Lung Transplant 34:233-40

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