Down syndrome (DS) is the most common human chromosomal anomaly and affects 1 in 800 newborns in the United States. Although Down syndrome can affect many organ systems, lung and heart disease are the leading causes of death at all ages in DS. Several congenital lung anomalies are reported in DS patients including airway branching defects, with a 25% decrease in number of branch generations, pulmonary hypoplasia, cystic lesions and vascular defects leading to pulmonary hypertension. In addition, DS patients can present with reduced upper airway muscle tone with dysphagia and/or bronchomalacia. We have developed a human ex vivo lung branching morphogenesis model that allows for branching quantification in real time, and in which we can interrogate the contributions of smooth muscle. Our preliminary data suggests that defects in SMC peristalsis appear to impair branching in human DS lung explants. We have also recently demonstrated the ability to transcriptionally profile mesenchymal smooth muscle cell diversity in normal human fetal lung tissues. Our preliminary data identify molecular markers unique to defined populations including vascular and airway smooth muscle cells. Therefore, we hypothesize that abnormal lung development in DS is caused by cell autonomous deficiencies in smooth muscle cell function, phenotype and heterogeneity.
In aim 1, we will test the hypothesis that airway branching-associated function and phenotype of lung SMCs is impaired in DS using our ex vivo fetal human lung culture system to further examine branching and peristalsis in DS fetal lung tissues. We will also test whether calcium-mediated changes in SMC contraction and peristalsis are normal in DS lung SMCs.
In aim 2, we will determine whether airway smooth muscle cell diversity is abnormal in DS fetal lung using single cell transcriptomics to assess the diversity of SMC phenotypes in normal and DS fetal lung. We will also define the specificity of any alterations by simultaneously comparing normal and DS lung vascular smooth muscle cell phenotypic heterogeneity. Our proposed studies will be the first to test novel hypotheses about primary deficiencies in early DS lung SMC phenotypes and function using cutting-edge methods that will provide insight at the physiological, morphogenic, cellular and molecular levels. Improved strategies to prevent, ameliorate or reverse lung disease in DS will be contingent upon a detailed understanding of the pathogenesis of these diseases. The studies proposed here are designed to provide fundamental knowledge about the abnormal pathophysiology contributing to developmental abnormalities in DS lung, and may identify therapeutic targets for intervention.
Several congenital lung anomalies are reported in Down syndrome patients including airway branching defects, with a 25% decrease in number of branch generations, pulmonary hypoplasia, cystic lesions, vascular defects and reduced upper airway muscle tone with dysphagia and/or bronchomalacia. We hypothesize that abnormal lung development in DS is caused by cell autonomous deficiencies in smooth muscle cell function, phenotype and heterogeneity. The studies proposed here are designed to provide fundamental knowledge about the abnormal pathophysiology contributing to developmental abnormalities in DS lung, and may identify therapeutic targets for intervention.
| Danopoulos, Soula; Thornton, Matthew E; Grubbs, Brendan H et al. (2018) Discordant roles for FGF ligands in lung branching morphogenesis between human and mouse. J Pathol : |
