Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia with a median survival time of 2-4 years after diagnosis. The alarming mortality rate is due to the lack of effective treatments. IPF is a chronic, fibrotic disease that is characterized by alveolar destruction due to increasing extracellular matrix deposition that leads to poor lung compliance, impaired gas exchange, and ultimately respiratory failure. Repetitive alveolar epithelial injury is a central process to the underlying pathology with injury to the alveolar stem-like cells, the type II alveolar epithelial cells (AECII) specifically, being a key player in the pathogenesis of IPF. Recent studies have shown that recapitulation of developmental genes in alveolar epithelium, specifically the AECII cells, is associated with the abnormal epithelial phenotype seen in IPF, however the mechanisms of how they alter epithelial function are poorly understood. One such developmental gene that we show to be inappropriately expressed in AECII in IPF is Sine Oculis Homeobox Homolog 1 (Six1), which is a transcription factor that is essential for normal lung morphogenesis in utero. We have demonstrated increased expression of Six1 in AECII isolated from patients with IPF. Furthemore, genetic deletion of Six1 in AECII using the tamoxifen-inducible cre-lox system protected mice from the development of fibrosis. Taken together these results point at an important role for Six1 in the development of fibrosis, yet the mechanisms are not fully understood. Understanding the exact mechanisms by which Six1 acts on the AECII cells will be key to the development of novel therapeutic targets and the advancement of the current scientific understanding of the progression of pulmonary fibrosis. In this proposal we aim for the first time to identify the mechanisms whereby Six1 modulates fibrosis.Thus, we propose to elaborate and evaluate these novel findings. We propose to identify the molecular mechanisms by which Six1 acts on AECII cells and how this contributes to the pathophysiology of pulmonary fibrosis with the hypothesis that increased Six1 expression in AECII cells contributes to the development of pulmonary fibrosis. This comprehensive study of the function of Six1 will be the first to characterize a role for Six1 in fibrosis. It will also provide the PI with substantial training and experience to become a productive and innovative physician-scientist in the future.
The alarming mortality rates and lack of effective treatments for patients with Idiopathic Pulmonary Fibrosis (IPF) is well recognized. Changes in lung cell biology and the reactivation of developmental genes in the alveolar type II cells (AECII) is seen as a driver of disease in IPF, however how these ?developmentally reprogrammed? cells promote the progression of IPF is not fully understood. I hypothesize that one developmental gene, Six1, contributes to the development of IPF and will determine how Six1 expression in AECII promotes lung fibrosis in order to identify novel therapies for IPF.
