Priming epithelial cell activation to regenerate the lung
Activity Code: ERC-SG-LS
Principal Investigator: Dr Dr Melanie Königshoff
Host Institution:Helmholtz Zentrum München- German Research Center for Environmental Health
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 initiating alveolar epithelial restoration, giving rise to new ATII cells or differentiating into ATI cells. Thus, 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 healthy and diseased lungs, and explore the regenerative potential of novel initiating and differentiating factors in vivo and ex vivo.
The WNT/?-catenin signaling is a promising initiating factor for lung regeneration. We have recently demonstrated a crucial role of WNT/?-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/?-catenin signaling in lung generation. Thus, we will explore WNT/?-catenin signaling in ATI and ATII cells, and the regenerative potential thereof. We will analyze the ATI and ATII 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 identified 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.
Funding Scheme: ERC Starting Grant 2010