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.
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