MORPHOMICS-IPF · A multi-layered -omics study to understand the dynamics leading to morphological progression in pulmonary fibrosis

A multi-layered -omics study to understand the dynamics leading to morphological progression in pulmonary fibrosis

Pulmonary fibrosis (PF) affects more than 500,000 patients in Europe yearly. Rather than a disease itself, it is regarded as a pathobiological mechanism present in multiple rare disease entities, causing excessive scarring in the lung tissue. This leads to architectural distortion, ultimately conferring respiratory failure and death in the vast majority of patients affected. Fascinatingly, some of the processes seen in the fibrotic lung are in se similar to physiological repair mechanisms. Indeed, the lung is a dynamic organ that is capable of lung repair upon injury in physiological conditions. However, in fibrotic interstitial lung diseases, these repair mechanisms appear aberrant and do not resolve. Rather than a linear trajectory of serial events, the pathophysiology of the disease is characterized by bi-directional activation of the main protagonists in multiple, partially overlapping feed forward loops, which we refer to as cell circuits. To understand the cellular circuits diverting the repair mechanisms to these progressive fibrogenesis processes, we developed an in-depth spatially and (pseudo-)temporally resolved multidimensional omics study set-up. By including multiple samples per fibrotic lung and by staging these samples using microCT, we can compare less affected with more affected lung zones thus modelling evolution through disease progression. After scanning and staging, a 4-dimensional -omics approach is applied: 1. single nucleus RNA sequencing 2. Spatial transcriptomics: using GeoMx© (Nanostring) 3. Spatially resolved laser-capture microdissection-based proteomics 4. Antibody-based proteomics: Iterative indirect immunofluorescence imaging data (4i) Immediate aims of the analysis project are to (1) map the evolution of epithelial and mesenchymal cell states, and (2) predict critical cell-cell communication events in the alveolar and terminal airway niches throughout the disease progression.

Data: CORDIS, © European Union