This application is a renewal for the P01 Program Project Grant ?Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease?. This was originally awarded with Dr. Paul Noble as the overall PI at Duke University in 8/12. The original application consisted of 3 overall projects, Project 1 (Dr. P. Noble), Project 2 (Dr. Jo Rae Wright, transferred to Dr. Barry Stripp), and Project 3 (Dr. Monica Kraft). Starting in January, 2013 upon moving Dr. Noble and Dr. Stripp?s research programs to CSMC, we initiated a collaboration with Dr. John Belperio at UCLA. The unifying theme of this Program Project Grant application is that crosstalk between the lung epithelium and underlying mesenchyme determines homeostasis versus disease in both pulmonary fibrosis and CLAD. The overarching hypothesis for this application is that both IPF and CLAD develop in response to epithelial cell dysfunction AND progenitor cell failure. A fascinating emerging biology is the relationship between the distal conducting airway epithelium and the distal alveolar epithelium. It is our contention that CLAD develops from a failure of conducting distal airway progenitor cells and IPF from distal alveolar epithelial cell failure. However, the loss of progenitor cell function in one compartment may well influence the other compartment. In response to the loss of epithelial cell homeostasis, there is activation and recruitment of a destructive mesenchymal cell population that takes on some features of metastasizing cancer cells, i.e., the ability to invade extracellular matrix. The final reason for the evolution in the application is the investigative team. We have assembled a team of investigators that have generated new ideas in lung biology, pioneered and partnered to achieve state of the art tools to address these new ideas and have a track record of success in both mechanistic animal studies as well as utilizing human tissue samples to advance our understanding of the pathogenesis of IPF and CLAD. In this Program, we propose a model for the initiation and perpetuation of fibrosis that emanates from progenitor cell dysfunction in the conducting airway epithelium (multiple progenitor cell types including club cells) in the case of CLAD, and the alveolar epithelium (alveolar type 2 cell- AT2 or AEC2) in the case of IPF leading to innate immune cell activation and the recruitment of a mesenchymal phenotype that is destructive and invasive. We have identified some common features in the pathobiology of CLAD and IPF as well as unique aspects. The common themes include the recruitment of an invasive fibroblast phenotype as defined by the ability to invade extracellular matrix (Project 1 ? Noble) and the interplay between p53 and IL-22 in regulating bronchiolar epithelial homeostasis (Project 2 ? Stripp and Project 3 ? Belperio).
This application is a renewal for the P01 Program Project Grant ?Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease?. The overarching hypothesis for this application is that both IPF and CLAD develop in response to epithelial cell dysfunction AND progenitor cell failure. The common themes include the recruitment of an invasive fibroblast phenotype as defined by the ability to invade extracellular matrix and the interplay between p53 and IL-22 in regulating bronchiolar epithelial homeostasis.
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