Research Project
10297761
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.
