DKK3 as master regulator of pulmonary regeneration – divergent roles in COPD vs. IPF

• Applicants: Professor Dr. Robert Bals; Professor Dr. Andreas Keller
• Subject Area: Pneumology, Thoracic Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544291623

Exposure of the lung to pathogens or toxins results in damage that is followed by repair mechanisms to secure adequate organ function. Defective regeneration leads to diseases such as fibrotic lung disease (FLD) or chronic obstructive lung disease (COPD). DKK3 is a signaling molecule that is produced by epithelial cells or the mesenchymal niche in response to injury. Preliminary own data showed that the DKK3 concentration is significantly decreased in the bronchoalveolar lavage of COPD patients, while it is increased in the BALF of patients with progressive FLD. Data from preclinical models highlight the role of DKK3 for epithelial repair and fibrogenesis. Depletion of DKK3 in a bleomycin lung fibrosis model blunts the development of disease development. We propose that endogenous expression of DKK3 in AT1/2 cells is an (autocrine) factor for the maintenance or repair. In addition, DKK3 secreted from pericytes / fibroblasts acts on epithelial cells to modulate differentiation. The aim of this project is to characterize the role of DKK3 in epithelial repair. This working program is subdivided in three specific aims: Specific aim 1: Characterization of DKK3-dependent cell interactions in preclinical murine models of COPD and FLD. Cell-type conditional knockout or overexpression of DKK3 are applied to identify the relevant spatial distribution of DKK3 activities. AT1/2 and pericyte/fibroblast-specific knockdown of DKK3 will be applied to identify the outcome in preclinical models of COPD and FLD. Specific aim 2: Spatio-temporal characterization of signaling in human and murine models of COPD and FLD in alveolar cell models. We will apply alveolar epithelial - fibroblast cocultures to investigate cell-cell interactions in human-based models. Here we will deplete or overexpress DKK3 in epithelial cells or fibroblasts and investigate cell differentiation and disease-specific transcriptome patterns. Time-course setup combined with single cell transcriptomics are applied to decipher multi-cellular responses to bleomycin- or cigarette-smoke-based models. Specific aim 3: Definition of the role of DKK3 in clinical investigation: progression of COPD and FLD. Tissue samples from patients (COPD, FLD) and healthy controls (cancer resection without COPD) will be used to characterize the spatial distribution of DKK3 expression together with up/downstream signaling by spatial single cell sequencing. Longitudinal follow up of clinical cohorts will allow to define the role of BALF DKK3 concentrations as biomarkers for disease progression. The project is based on the complementary expertise of Prof. Bals and Prof. Keller. The data obtained in this study will show how DKK3 is involved in the regulation of the lung and the pathogenesis of lung disease. We also evaluate whether DKK3 can be applied as a biomarker.

• DFG Programme: Research Grants