Breaking barriers: new insights into the contribution of the protocadherin-1 (PCDH1) gene in asthma

Asthma is a global health problem affecting 1-18% of the population worldwide. This heterogeneous disease is characterized by chronic inflammation of the airways that can be treated but not cured. Asthma is caused by a combination of environmental and genetic factors. Many asthma genes are expressed in the airway epithelium, highlighting the importance of the airway epithelium in the development of asthma.
In this thesis, we investigated the role of Protocadherin-1 (PCDH1), a novel asthma and bronchial hyperresponsiveness gene, in the airway epithelium. The PCDH1 gene encodes a putative adhesion molecule which at the start of this research project was considered of unknown function. We hypothesized that dysfunction of PCDH1 compromises the barrier function of the airway epithelium, thereby contributing to asthma susceptibility. The studies in this thesis investigated the potential mechanisms by which asthma-associated PCDH1 gene variants alter PCDH1 DNA methylation and its expression; and describe the role of PCDH1 as an adhesion molecule: loss of PCDH1 expression compromised the epithelial barrier. Finally, we describe the interaction of PCDH1 with SMAD3, another important asthma gene, that plays a role in the remodeling of the airways.
Shedding some light into the role of PCDH1 in epithelial barrier formation and repair is necessary to develop therapies that can prevent airway remodeling and promote normal epithelial repair.