Chronic obstructive pulmonary disease (COPD), a global health problem, will be the third leading cause of death by 2020. No effective therapy exists for COPD, which is characterized by a progressive loss of lung tissue, in particular functional alveolar epithelium, due to the inability of the lung to regenerate. Thus, regeneration of functional lung tissue would be a tremendous step forward, which has not been demonstrated as of yet.The alveolar epithelium is essential for normal lung function and composed of alveolar type I (ATI) and type II (ATII) cells. ATII cells serve as progenitors for alveolar epithelial restoration via differentiation into ATI cells. Induction of lung regeneration requires a tight interplay between initiating and differentiating factors acting on the alveolar epithelium.The overall aim of this proposal is to explore the regenerative potential of the adult human lung, driven by the alveolar epithelium. We will utilize an ex vivo lung regeneration model, characterize ATI/II cells in diseased lungs, and explore novel initiating and differentiating factors in vivo and ex vivo.WNT/²-catenin signaling is a promising initiating factor for lung regeneration. We have recently demonstrated a crucial role of WNT/²-catenin signaling in alveolar epithelial cell repair in lung disease. Further, embryos lacking WNT2/2b expression exhibited complete lung agenesis, demonstrating the requirement of WNT/²-catenin signaling in lung generation. We will explore WNT/²-catenin signaling in ATI/II cells, and the regenerative potential thereof. We will analyze the ATI/II cell phenotype in mouse and human COPD specimen, to identify novel differentiation factors facilitating lung regeneration.We will consolidate our findings by testing the therapeutic applicability of initiating and differentiating factors in COPD in our ex vivo human lung regeneration model. This will lead to reliable and validated results that will be successfully translated into the clinic.