Cellular Senescence in Trisomy 21 lung disease

SUMMARY Trisomy 21 (T21) occurs in ~1 in 700 live births resulting in Down Syndrome (DS), where pulmonary complications are the main cause of hospitalizations in children and adults. These include tracheobronchial diseases presenting as decreased upper airway muscle tone, tracheobronchial malacia and airway obstruction with wheezing, particularly in babies and children. There is currently limited to no information regarding the pathogenesis of primary lung disease in DS. Thus, understanding early, perinatal factors leading to lung disease in neonates and children with DS becomes clinically relevant and innovative with potential for substantial lifelong impact. Senescent (Sen) cells in G1 cell cycle arrest secrete factors (Sen-associated secretory phenotype; SASP) that mediate paracrine effects on naïve cells. Sen can be induced by DNA damage, oxidative stress and mitochondrial dysfunction, all of which are increased in T21. While Sen can be beneficial in growth and repair, it becomes detrimental when Sen cell numbers exceed immune clearance (defective in T21), and secrete a pro- inflammatory, pro-fibrotic SASP that maintains and expands detrimental Sen. Maintenance of SASP, known as late Sen, is modulated by IFN-I signaling, a pathway consistently activated in T21. Thus, if DS is seen as a form of progeria (early aging) involving Sen, there is strong premise to link Sen, IFN-I and T21. These relationships are entirely unknown in the DS lung, especially in prenatal/early postnatal life when the potential for impactful intervention is high. Here, drugs that kill Sen cells (senolytics) such as Dasatinib + quercetin (D+Q), or fisetin (flavonoid in strawberries), or even SASP modulators (senomorphics) represent novel therapies that are only recently being tested in lung diseases. Our key preliminary data show increased baseline Sen in T21 fetal lung tissues and mesenchymal cells (FLMC). We hypothesize that detrimental Sen/SASP present in T21 initiates in utero and promotes lung disease in DS; effects alleviated by senolytics and senomorphics. Our approach will be to use developing human lung tissues, mesenchymal cells and ex vivo explant models from T21 and non-T21 fetal, neonatal and pediatric samples to determine the impact of Sen in T21, the interplay between T21 and IFN- I and the possible effects of senolytics and senomorphics towards therapies for lung disease in DS. Our proposal represents a novel approach to understanding and treating lung disease in a highly vulnerable population where pulmonary disorders represent a major healthcare issue, yet with little to no information regarding disease pathogenesis.