Organ Ageing and Remodelling.
Description: Pulmonary diseases are a major cause of morbidity and mortality. A diversity of different lung diseases exists each associated with their own presentation, prognosis, and pathophysiologic mechanisms. Leveraging a macro to micro approach using state-of-the-art technologies such as HiP-CT, microCT and spatial transcriptome analysis on wellcharacterized human lungs and innovative animal models such as primary bronchial epithelial culture and a murine lung transplant model, the aim of this application is to better diagnose and better understand the pathophysiological mechanisms of lung diseases. Several topics are detailed where the overall aim is to improve the diagnosis of lung disease. Firstly, we seek to consolidate the tumor classification of surgically resected lung lobes more adequately by investigating micro-lesions in the lung. Secondly, we want to assess suitability of donor lungs for lung transplantation via ex vivo imaging. Thirdly, we aim to find better markers of small airway disease in patients with smoking induced lung changes. Fourthly, we seek to directly correlate in vivo CT data to ex vivo histological and functional data to construct a virtual biopsy. Next to better diagnosis, it is also important to improve the knowledge on the pathophysiological mechanisms of lung diseases. Therefore, the morphological changes and pathophysiological mechanisms of several lung diseases will be further explored in comparison to physiological lung aging. HiP-CT analysis will be used on aging and end-stage lung specimens to provide an unprecedented view on the bronchial and vasculature changes at extreme high resolution on an entire specimen. As this approach is logistically difficult in early disease specimens, microCT will be used to compare bronchial and vasculature changes in early to late-stage disease and aging. To further investigate the mechanisms of this lung remodeling, primary bronchial epithelial cells will be harvested and used to investigate the immunoreactivity to infectious and non-infectious triggers. The lung tissue itself will also be subjected to in-depth investigation by staining for different inflammatory markers, by scanning electron microscopy to investigate collateral ventilation and by spatial transcriptome/single nuclear sequencing analysis. Lastly, the role of microvascular alterations will be further investigated using a murine orthotopic lung transplant model where the sequence of vascular changes will be investigated via bulk transcriptome analysis and in/ex vivo imaging techniques. Lastly, pharmacological inhibition will be attempted to confirm the involvement of the microvasculature. Ultimately, this ambitious and innovative project will lead to tremendous new insights which could help in the diagnosis of (early stage) lung disease and will definitely be important to better understand the pathophysiology of respiratory diseases. This will assist in assessing disease prognosis and eventually therapy, which is desperately needed given the high- morbidity and mortality of lung diseases.
Funder: Vlaamse regering
Funding type: grant
Funder scheme: BOF - projects
Start date: 2023-10-01
End date: 2028-09-30
Investigator: Stijn Verleden
Institution: UAntwerpen
Funded outputs count: 0
Funder award ID: vlaamse-514440c8-2049-4f8d-a64b-2223721e8907
OpenAlex ID: G4026508109