Fachbereichskolloquium: Einladung zum Doppelvortrag

Cancer is a major, global factor for human lethality. Mutations in the metabolic enzyme isocitrate dehydrogenase-1 (IDH1), a part of the tricarboxylic acid cycle during cellular respiration, are intimately linked to the development of severe forms of cancer such as glioblastoma, acute myeloid leukaemia, intrahepatic cholangiocarcinoma and melanoma.

In this talk, insights into the molecular mechanisms of mutated IDH1 will be presented, which critically contribute to tumorigenesis. Particular focus will be put on structure-function studies of changes in the interactome of mutated IDH1 and the search for specific inhibitors to counteract the consequences of the disease-related mutations.

The epithelial sodium channel (ENaC) plays a key role in salt homeostasis in mammals. Four ENaC subunits (α, β, γ, δ) form heterotrimeric αβγ- or δβγ-ENaCs. While the physiology of αβγ-ENaCs is well understood, the function of δβγ-ENaC is unknown. No standard laboratory animal model is available for studying δ-ENaC physiology as the SCNN1D gene (encoding δ-ENaC) is absent in rats and mice. C. porcellus (guinea pig) has an intact SCNN1D gene. Functional characterisation of guinea pig αβγ- and δβγ-ENaC provides the first evidence of two functional isoforms in rodents. Guinea pig αβγ- and δβγ-ENaC have similar biophysical and regulatory features to their respective human ENaC orthologues. Thus, guinea pigs represent a commercially available rodent model that allows the investigation of δ‑ENaC in mammals.

Additionally, through contributing to airway surface liquid homeostasis, αβγ-ENaC represents a valuable therapeutic target to rehydrate the airway surface liquid. Overexpression of the β-ENaC subunit in the airways of mice (β-ENaC-tg) causes sodium hyperabsorption and airway surface liquid dehydration causing a pulmonary phenotype similar to chronic obstructive pulmonary disease and cystic fibrosis.

However, the long-term consequences of β-ENaC overexpression in the airways remain unknown. To best utilise this model in the development of therapeutic drugs we sought to answer this question. Through the application of longitudinal micro-computed tomography (µ-CT), we noninvasively recorded the pulmonary pathological hallmarks of β-ENaC overexpression. Interestingly, the development of emphysema represented a robust and reliable biomarker of disease progression in β-ENaC-tg mice. µ-CT findings were cross-validated with lung function analysis and histological staining to confirm the progression and severity of emphysema. Together these data suggest an initial active stage and a passive stage in the pathogenesis of β-ENaC-tg mice and define a window for therapeutic intervention. This research demonstrates that β-ENaC-tg mice represent a valuable model for studying diseases involving airway surface liquid dehydration and the development of ENaC targeted therapeutic drugs.