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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130984-05
Application #
9859426
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Charette, Marc F
Project Start
2016-04-15
Project End
2021-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Pediatrics
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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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Trzepizur, Wojciech; Cortese, Rene; Gozal, David (2018) Murine models of sleep apnea: functional implications of altered macrophage polarity and epigenetic modifications in adipose and vascular tissues. Metabolism 84:44-55
Macey, Paul M; Kheirandish-Gozal, Leila; Prasad, Janani P et al. (2018) Altered Regional Brain Cortical Thickness in Pediatric Obstructive Sleep Apnea. Front Neurol 9:4
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Khalyfa, Abdelnaby; Gozal, David; Kheirandish-Gozal, Leila (2018) Plasma Exosomes Disrupt the Blood-Brain Barrier in Children with Obstructive Sleep Apnea and Neurocognitive Deficits. Am J Respir Crit Care Med 197:1073-1076
Khalyfa, Abdelnaby; Gozal, David; Masa, Juan F et al. (2018) Sleep-disordered breathing, circulating exosomes, and insulin sensitivity in adipocytes. Int J Obes (Lond) 42:1127-1139
Suarez-Giron, Monique C; Castro-Grattoni, Anabel; Torres, Marta et al. (2018) Acetylsalicylic Acid Prevents Intermittent Hypoxia-Induced Vascular Remodeling in a Murine Model of Sleep Apnea. Front Physiol 9:600
Smith, Dale L; Gozal, David; Hunter, Scott J et al. (2017) Parent-Reported Behavioral and Psychiatric Problems Mediate the Relationship between Sleep-Disordered Breathing and Cognitive Deficits in School-Aged Children. Front Neurol 8:410
Hornero, Roberto; Kheirandish-Gozal, Leila; GutiƩrrez-Tobal, Gonzalo C et al. (2017) Nocturnal Oximetry-based Evaluation of Habitually Snoring Children. Am J Respir Crit Care Med 196:1591-1598

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