PROJECT SUMMARY – ABSTRACT
Coatomer protein subunit alpha (COPA) syndrome is a rare, autosomal dominant, monogenic disorder that
results in a multiorgan disease affecting the lungs and joints with incomplete penetrance. Patients present early
in life with interstitial lung disease (ILD) and have elevated inflammatory markers and positive autoantibody titers.
While treatments exist to control this aberrant immune phenotype, they do not address the unknown
mechanism(s) of this disease. COPalpha is a ubiquitously expressed subunit of the coatomer protein complex I
(COPI) which is responsible for retrograde transport of proteins from the Golgi to the ER. Alterations or
disruptions in this pathway result in cellular stress. To date, most studies have examined the role of the immune
system in the onset and progression of COPA syndrome without elucidating a cause for this disease. Therefore,
we believe other cell types and processes are involved. Most COPA patients will at some point suffer from a
spectrum of pulmonary disease such as bronchiolitis, ILD, and/or pulmonary fibrosis (PF). These diseases share
certain pathogenic characteristics in response to cellular stress including, but not limited to, ER stress and
unfolded protein response (UPR) activation, activated fibroblasts, inflammation, and aberrant autophagy.
Progenitor cells of the proximal and distal lung, basal and alveolar type II cells (ATII), respectively, are
disproportionally affected causing aberrant maintenance of the epithelium throughout the airway. We believe
similar mechanisms of progenitor cell dysfunction are occurring in COPA syndrome patients. We therefore
hypothesize that COPA syndrome is driven by an intrinsic progenitor cell defect that compromises
epithelial maintenance resulting in ILD and lung fibrosis. In Aim 1, we will determine the epithelial cell-
intrinsic defects resulting from the expression of COPAMT. This will be achieved by characterizing the COPalpha interactome to elucidate anomalous protein interactions leading to cellular stress. We will then characterize the
transcriptome of COPAMT using single cell RNA sequencing to highlight differential gene expression patters
associated with disease. Furthermore, we will utilize in vivo mouse models to accurately describe the link
between pulmonary progenitor cell dysfunction and activation of the immune responses associated with COPA
syndrome. In Aim 2, we will validate strategies to rescue the epithelial cell defect of COPA syndrome using
lentiviral vector delivery systems and gene editing tools with the intention of rescuing the diseased phenotype.