Over the last decade, we and others have uncovered the presence of multisystem morbidity associated with pediatric obstructive sleep apnea (OSA), obesity, or the combination thereof. Among the several important morbid consequences, neurocognitive deficits NC-D(+) were identified, and exhibited disease severity related prevalence changes with significant interactions between OSA and obesity. However, at any level of OSA severity, obesity, or both, there will be children with NC-D(+) and those without. Most recently, we have identified that children with NC-D(+) have circulating exosomes that exhibit unique miRNA signatures and that such exosomes disrupt an in vitro model of the blood brain barrier (BBB). We therefore hypothesized that in children with sleep-disordered breathing (SDB) and NC-D(+) circulating plasma exosomes will display unique miRNA signatures that elicit in vitro BBB dysfunction. To confirm such hypothesis we propose to investigate whether plasma exosomes in non-obese children (SA#1) and obese children (SA#2) with and without OSA and NC-D(+) differ from age, sex, and ethnicity-matched non- obese or obese children with and without OSA and NC(-) in the following: (a) Cell source and miRNA cargo; (b) In vitro disruption properties of the BBB; (c) In vivo alterations in BBB permeability in a murine model. We further aim to explore whether use of mimic miRNAs or siRNAs of the previously identified differentially expressed miRNAs in exosomes can reverse or accentuate in vitro and in vivo disruption of the BBB (SA#3), and also determine whether adenotonsillectomy treatment of non-obese and obese children with OSA and NC-D(+) leads to changes in plasma exosomal miRNA signatures and biological properties that reflect temporal changes in BBB (SA#4). These studies will not only identify for the first time the unique potential biomarker value of miRNAs in the exosomal cargo along with identification of their putative gene targets and biological roles in BBB and cognitive function, but will also enable a better understanding of the mechanisms underlying the higher risk for neurocognitive dysfunction associated with both pediatric obesity and OSA, and potentially permit development of miRNA targeted therapeutic approaches to prevent the important long-term complications of these prevalent pediatric disorders.

Public Health Relevance

Children with OSA are at increased risk for endothelial and cognitive dysfunction. We hypothesize that selected microRNAs in plasma exosomes disrupt the function of the blood brain barrier and could be the cause of such dysfunction enabling us to identify children at risk and potentially develop new therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Charette, Marc F
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University of Missouri-Columbia
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Khalyfa, Abdelnaby; Kheirandish-Gozal, Leila; Gozal, David (2018) Circulating exosomes in obstructive sleep apnea as phenotypic biomarkers and mechanistic messengers of end-organ morbidity. Respir Physiol Neurobiol 256:143-156
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