Project Summary/Abstract
Down syndrome (DS), also referred to as trisomy 21, is the most common human chromosomal anomaly,
affecting 1 in 700 live births. Although DS can affect many organ systems, lung and heart disease are the leading
causes of morbidity and mortality. Several congenital lung anomalies are reported in individuals with DS including
airway branching defects, with a 25% decrease in the number of branches and reduced upper airway muscle
tone with dysphagia and/or bronchomalacia. These complications remain constant into adulthood, as opposed
to becoming exacerbated, and are hence likely due to developmental insufficiency.
While abnormal pulmonary structure and function in pediatric and adult DS subjects has been described, there
is limited data defining the ontogeny of these abnormalities. We postulated that some developmental differences
could initiate prenatally. Preliminary data developed for this application shows that DS fetal lungs, starting as
early as 16 weeks gestation, present with pronounced dilatation of terminal airways/acinar tubules, dilated
lymphatics and muscularized arteries. In addition, we find increased lung expression of type I IFN signaling target
genes such as MX1 and IFI27 in DS compared to non-DS fetal lungs. IFN signaling plays a critical role in cell
differentiation, proliferation, apoptosis, and ECM production, important events for lung development. Finally, our
preliminary data show that DS lungs exhibit altered expression of ECM affiliated proteins, regulators, and
secreted factors (FN1, COL6, etc.). Therefore, we hypothesize that lung defects in DS can initiate during fetal
development, and that IFN-dependent changes in cell proliferation, differentiation and ECM production contribute
to these defects. To test this hypothesis, we will 1) Test the hypothesis that morphological, cellular and molecular
abnormalities are initiated during the late pseudoglandular/early canalicular stages of fetal development in DS
lungs using histopathological analyses and single cell sequencing, 2) Test the hypothesis that excessive type I
IFN signaling disrupts cell differentiation and airway branching during fetal lung development in DS, and 3) Test
the hypothesis that excessive IFN signaling disrupts ECM production during fetal lung development in DS. For
aims 2 and 3, we will use our published fetal lung explants culture model as well as epithelial organoid cultures
alone or co-cultured with mesenchymal cells to test the effect of gain and loss of function of type I IFN signaling
on cell differentiation and ECM production.
These studies have the promise to improve our understanding of the key molecular and cellular differences, and
the mechanisms controlling branching defects in DS developing lungs. The innovative aspects of this work are
likely to have great overall impact and facilitate the translational potential for therapies for DS individuals, as well
as other lung congenital defects demonstrating hypoplastic lungs.
