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DOI: 10.1055/s-0039-1678386
The Role of Serine Peptidase Inhibitor Gene Variants in Asthma Development
Publication History
Publication Date:
15 February 2019 (online)
Instruction Bronchial asthma is a chronic inflammatory airway disease caused by a complex interaction
between an individualʼs genetic make-up and the environment. Along this line, genetic
studies have shown that variants in the serine peptidase inhibitor gene (serpin) scca1
are associated with asthma. However, the functional role of these variants (GV) is
unknown.
Aim Therefore, we aim at deciphering the pathophysiological role of scca1 GV in asthma.
To achieve this, we are exploring whether ssca1 GV increase the susceptibility towards
common risk factors (hypoxia, tobacco smoke) and whether they affect airway epithelial
barrier functions (structure, integrity and immune defence).
Methods The flyʼs orthologous of scca1 have been identified based on amino acid similarity
and the presence of one serine protease inhibitor domain. By using the Gal4/UAS system,
fly models (overexpression/RNAi models) dysexpressing scca1 in the airway epithelium
were successfully established. To figure out if scca1 dysregulation affects airway
morphology, the number and length of secondary branches in 1st and 3rd instar larvae
were assessed. 3rd instar larvae were then exposed to hypoxia (5% O2) for two hours. Larval crawling activity (a measure for hypoxic stress) was determined
every ten minutes during hypoxia. Developmental period and mortality were assessed
by counting the number of pupae and adult flies at different time points after HE.
Results Airway-specific overexpression of scca1 led to an increased number of secondary branches
whereas its downregulation caused an increase in airway length. Moreover, dysexpression
of scca1 resulted in a high vulnerability towards hypoxic stress within the first
30 minutes of exposure. Additionally, an exposure to acute hypoxia significantly increased
adult but not pupal mortality of animals with reduced scca1 expression. While scca1
dysexpressing animals generally showed a developmental delay of pupae as well as adults,
additional exposure to hypoxia does not affect the developmental period of both stages.
In summary, we developed a Drosophila model for scca1, which is characterised by an
altered airway structure. These airway alterations could be responsible for an impaired
adaptability towards environmental stressors. Upcoming experiments will cover a more
detailed analysis of molecular mechanisms underlying pathophysiological alterations
of the airways due to scca1 dysregulation.
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