The role of Muc5b in lung homeostasis and onset and progression of interstitial lung disease

Student

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Mucociliary clearance is the primary innate defense mechanism of the lung and crucial to maintain lung homeostasis and health. Mucociliary clearance relies on motile cilia on the surface of epithelial cells and a protective mucus gel layer entrapping particles and pathogens to be cleared from the lungs. Recent evidence suggests that the secreted mucin MUC5B that is crucial for the formation of the mucus gel and proper mucociliary clearance is also implicated in the pathogenesis of interstitial lung disease (ILD).¹ ILD can affect children and adults and is characterized by interstitial inflammation, rapid progression of pulmonary fibrosis and subsequent disruption of the alveolar gas exchange ultimately leading to respiratory failure. The understanding of the pathogenesis remains limited and ILD is usually diagnosed in advanced stages when irreversible lung damage has already occurred. Further, only limited therapeutic options are available, which so far, cannot prevent progression of pulmonary fibrosis. By conditional deletion of Nedd4-2 (Nedd4-2^-/-) in lung epithelial cells of mice, we recently generated the first mouse model that develops spontaneous pulmonary fibrosis sharing key features with ILD patients allowing us to study lung homeostasis at baseline and early dysregulation leading to the development of interstitial lung disease.^2,3

Project description:

The aim of this translational research project is to investigate the role of Muc5b in the onset and progression of interstitial lung disease in conditional Nedd4-2^-/- mice. For this purpose, double knockout mice deficient for Nedd4‑2 and Muc5b will be generated and their lung phenotype comprehensively studied at different stages of disease progression to identify early changes in lung homeostasis and pathways that promote disease progression and may serve as therapeutic targets. Clinical parameters such as inflammation markers, histology, lung function, as well as mucus properties will be investigated in order to gain insight into the relationship between altered mucus properties and disease pathogenesis. Further, our findings will be validated in lung biopsies and serum samples from patients with ILD. In addition to basic molecular biology laboratory work, this experimental MD thesis also applies state-of-the-art mouse lung function, mucus rheological measurements, and high content microscopy.

References

1. Evans CM, Fingerlin TE, Schwarz MI, […], Warg L, Yang IV, Schwartz DA. Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways. Physiol Rev. 2016; 96:1567-1591. doi: 10.1152/physrev.00004.2016.
2. Duerr J, Leitz DHW, Szczygiel M, […], Beers MF, Klingmüller U, Mall MA. Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice. Nat Commun. 2020; 11:2012. doi: 10.1038/s41467-020-15743-6.
3. Leitz DHW., Duerr J, Mulugeta S, […], Dalpke AH, Beers MF, Mall MA. Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice. Int J Mol Sci. 2021; 22:6146. doi: 10.3390/ijms22116146.