The long-term goal of the investigator is to become a productive and independent clinician scientist with a well- funded laboratory focused on lung transplantation research. The immediate goal of the investigator is to acquire the skill set necessary to become an independent investigator. This proposal focuses on understanding the pathogenesis of obliterative bronchiolitis (OB) that develops in 50% of the recipients following lung transplantation within 5 years. We have developed a model of orthotopic left lung transplant that reproduces all aspect of human lung transplant histopathology, including development of OB. Using this novel model we propose to investigate whether airway epithelial stem cells respond abnormally following lung transplantation and to determine if this abnormal response contributes to the development of OB. Specifically, this proposal will focus on the contribution of denervation to aberrant calcitonin gene related peptide (CGRP) neuropeptide responses that control stem cell proliferation in the airways. The investigator's mentor, Dr. John Engelhardt, has a long-standing history in studying stem/progenitor cells in the lung and has studied airway biology in the ferret for more than a decade. Lung transplantation is a major treatment option for end-stage lung diseases. OB, which is considered to be a form of chronic rejection in the transplanted lung, prevents long-term survival as it affects almost one out of two recipients by five years. Once OB sets in the allograft, it is progressively fatal and there is no effective treatment available. The mechanisms that cause OB are unclear and it has been proposed that epithelial stem cell depletion may be a contributing factor. However, there is currently no research being done to test this hypothesis. We recently developed an orthotopic lung transplant model in the ferret that develops classic OB. We have also shown that CGRP, a known marker for the stem/progenitor celI niches in the distal airways, promotes proliferation and differentiation of slow-cycling airway stem cells into transient-amplifying cells with limited proliferative capacity. In this proposal we will address the following hypotheses: 1) In a transplanted lung, epithelial injury results in the aberrant recruitment and proliferation of slow- cycling stem cells at different sites within the donor lung/allograft. 2) In a transplanted lung, he CGRP response to injury is dysregulated due to the lack of innervation. 3) In a transplanted lung, dysregulation of CGRP levels leads to exhaustion of slow-cycling stem cells in the distal airways and, ultimately, an aberrant injury response. We expect that understanding the epithelial stem cells injury responses in the transplanted lung will clarify the pathogenesis of OB and thereby provide an opportunity to prevent or delay the development of OB in the allografts. Furthermore, our proposal will address several basic biologic questions about how innervations controls stem cell injury responses in the lung through neuropeptide signals. Such information may also be generally useful to the field of lung biology.
Lung transplantation is a viable treatment option for a variety of end-stage lung diseases. However, long-term survival following lung transplantation is limited by development of obliterative bronchiolitis (OB) in the allografts that is irreversible and unresponsive to therapy. Approximately 50% of the lung transplant recipients are affected by OB within 5 years of transplantation. Progress in the effective management of OB has been limited due to lack of appropriate animal models that reproduce the human OB phenotype in lung allografts. We have developed a ferret orthotopic lung transplant model that develops OB and will use this model to investigate how stem cells respond to injury in the transplanted lung. We will test the hypothesis that depletion of airway stem cells contributes to the development of OB in the allograft.
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