Bronchiolitis Obliterans Syndrome (BOS) is the major cause of mortality after lung transplantation. Failure of immunosuppressive or anti-inflammatory therapies to meaningfully prevent or attenuate the course of the disease has focused attention on the role of fibroproliferation in its pathogenesis. Such a paradigm might involve an imbalance favoring pro-fibrotic over anti-fibrotic mediators, leading to fibroblast recruitment, proliferation and change in phenotype to more aggressive myofibroblasts with a high capacity for collagen synthesis. We have made the novel observation that fibroblasts can be cultured from the bronchoalveolar lavage fluid (BALF) of lung transplant recipients and appear to display an activated phenotype in cases with BOS. We hypothesize that the development of a pro-fibrotic milieu (increased ratio of BALF levels of pro- to anti-fibrotic mediators) and phenotypic alteration in fibroblasts are pivotal events in the clinical development of BOS. To test this hypothesis we will first study the levels of relevant pro- and anti- fibrotic biomarkers and the phenotype of fibroblasts in a cohort of patients with BOS and compare them to non-BOS patients (case control study, Aim 1). Second, in order to study such associations over time and the temporal sequence of events, we will serially measure these biomarkers and study phenotypic characteristics of fibroblasts longitudinally in a population of patients following lung transplant (prospective cohort study, Aim 2). This award will provide an opportunity for the Principal investigator to develop a career as a clinical researcher with expertise in translational studies in lung transplantation. A K-23 would provide the additional experience, didactic training and mentorship necessary to develop the skills necessary to transition to an independently funded investigator. An integral component of the training plan will include advanced didactic training in missing data management, longitudinal data analysis, sequential monitoring of survival endpoints and nonparametric survival analysis. These modalities of data analysis will be utilized to carry out the specific aims, thus providing practical experience to the candidate. Furthermore, the candidate will be directly mentored by one on one sessions with the co-mentors, Fernando J. Martinez MD, MS and Marc Peters-Golden MD, both of whom are well-funded researchers with a long track record of mentoring.
