The overall goal of this award is to enhance the ability of the applicant to train, mentor and support the career development of physician scientists pursuing translational patient oriented research in pulmonary medicine. This goal will be accomplished through a sustained reduction in the applicant's clinical and administrative responsibilities with a corresponding increase in effort spent on research and mentoring activities. The applicant's successful research program which is investigating the genetic basis for pulmonary allograft dysfunction will be used to provide trainees with an intensive research experience complemented by career development activities specific to each trainee including didactic coursework, research seminars and grant writing workshops. Although the mechanisms responsible for graft failure or rejection after lung transplantation are unknown, we believe the constant interplay between environmental stimuli and the transplant allograft drives the activation of innate pulmonary host defenses and that innate immune pathway activation in the transplanted lung promotes the development of posttransplant graft failure and rejection. In this project, we will specifically test the hypothesis that polymorphisms in donor or recipient innate immune receptors and signaling proteins determine patient susceptibility to primary graft failure or rejection after lung transplantation. Support for this hypothesis is provided by our preliminary studies in human lung transplant recipients which demonstrate that polymorphisms in the innate immune receptors TLR4 and CD14 significantly alter the risk for graft failure or rejection. Further support for this hypothesis is provided by our similar results in a murine transplant model. We will specifically 1) determine if single nucleotide polymorphisms (SNPs) in innate immune candidate genes of the donor or recipient are associated with the development of primary graft dysfunction 2) determine if SNPs in innate immune candidate genes of the donor or recipient are associated with the development of acute rejection and 3) determine if SNPs in innate immune candidate genes of the donor or recipient are associated with the development of chronic rejection in 1000 lung transplant subjects. Knowledge gained from these studies will enhance our understanding of the role for innate immune mechanisms in the development of posttransplant graft dysfunction and identify novel therapeutic targets to prevent complications after human lung transplant.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Petrovski, Slavé; Todd, Jamie L; Durheim, Michael T et al. (2017) An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis. Am J Respir Crit Care Med 196:82-93
Gowdy, Kymberly M; Martinu, Tereza; Nugent, Julia L et al. (2015) Impaired CD8(+) T cell immunity after allogeneic bone marrow transplantation leads to persistent and severe respiratory viral infection. Transpl Immunol 32:51-60
Verleden, S E; Todd, J L; Sato, M et al. (2015) Impact of CLAD Phenotype on Survival After Lung Retransplantation: A Multicenter Study. Am J Transplant 15:2223-30
Martinu, Tereza; Kinnier, Christine V; Sun, Jesse et al. (2014) Allogeneic splenocyte transfer and lipopolysaccharide inhalations induce differential T cell expansion and lung injury: a novel model of pulmonary graft-versus-host disease. PLoS One 9:e97951
George, M Patricia; Masur, Henry; Norris, Karen A et al. (2014) Infections in the immunosuppressed host. Ann Am Thorac Soc 11 Suppl 4:S211-20
Stober, Vandy P; Szczesniak, Christopher; Childress, Quiana et al. (2014) Bronchial epithelial injury in the context of alloimmunity promotes lymphocytic bronchiolitis through hyaluronan expression. Am J Physiol Lung Cell Mol Physiol 306:L1045-55
Martinu, Tereza; Gowdy, Kymberly M; Nugent, Julia L et al. (2014) Role of C-C motif ligand 2 and C-C motif receptor 2 in murine pulmonary graft-versus-host disease after lipopolysaccharide inhalations. Am J Respir Cell Mol Biol 51:810-21
Finlen Copeland, C Ashley; Vock, David M; Pieper, Karen et al. (2013) Impact of lung transplantation on recipient quality of life: a serial, prospective, multicenter analysis through the first posttransplant year. Chest 143:744-750
Shofer, S L; Wahidi, M M; Davis, W A et al. (2013) Significance of and risk factors for the development of central airway stenosis after lung transplantation. Am J Transplant 13:383-9
Castleberry, Anthony W; Worni, Mathias; Kuchibhatla, Maragatha et al. (2013) A comparative analysis of bronchial stricture after lung transplantation in recipients with and without early acute rejection. Ann Thorac Surg 96:1008-17; discussion 1017-8

Showing the most recent 10 out of 32 publications