Obstructive sleep apnea syndrome (OSAS), the most severe form of sleep disordered breathing (SDB), is a condition characterized by repeated episodes of intermittent hypoxia (IH) that frequently imposes substantial neurocognitive morbidities in humans. Rodent models have demonstrated that IH is associated with behavioral learning and memory deficits that are preceded by neurodegenerative changes in the hippocampus and cortex. Activation of the enzyme NADPH oxidase, a major source of superoxide radicals, may underlie many of the IH-induced oxidative modifications and contribute to the behavioral and neuronal consequences of IH. Recent evidence also indicates that consumptions of a diet high in fat and sugar, a major cause of obesity, not only enhances susceptibility to neuronal injury but increases activation of NADPH oxidase, suggesting that diet and IH may increase oxidative stress through a common pathway. Given that the obesity is a major risk factor for OSAS, it is imperative to identify the underlying factors that contribute to the neurocognitive morbidities associated with the disease implications. To test the hypothesis that IH and diet, a primary environmental cause of obesity, modulate neuronal susceptibility to IH, three major specific aims will be examined in an adult mouse model using as using Morris water maze task paradigms, changes in NADPH oxidase gene and protein expression, markers of oxidative stress, and apoptosis as follows: (1) The effect of genetic absence of NADPH oxidase activity (gp91phox-/- mice) on the behavioral and neuronal susceptibility to 14 days of intermittent daytime hypoxia (IH);(2) The effect of administration of apocynin, an inhibitor of assembly of the NADPH oxidase complex, on the behavioral and neuronal susceptibility to 14 days of intermittent daytime hypoxia (IH);(3) To determine if a long-term high fat/refined carbohydrate (HFRC) diet increases the behavioral and neuronal susceptibility of adult male mice to IH, and whether these deficits are prevented by the absence of NADPH activity (gp91phox-/- mice), and/or apocynin, an inhibitor of assembly of the NADPH oxidase complex. These studies will provide insight into the potential mechanisms which underlie the effects of IH on neuronal function, as well as the manner whereby environmental factors influence the pathogenesis of OSAS-associated cognitive deficits.

Public Health Relevance

Obstructive sleep apnea syndrome (OSAS), the most severe form of sleep disordered breathing (SDB), is frequently associated with cognitive deficits in humans and is currently estimated to affect as many as 18 million individuals in the United States alone. Substantial variability in the neurobehavioral outcomes of patients with sleep apnea suggest that both intrinsic (i.e., genetically-determined) or extrinsic (i.e., environmentally acquired) elements modify the behavioral susceptibility to sleep apnea. The studies in the present application will utilize a mouse model of the nocturnal breathing patterns of OSAS patients to not only provide information as to the potential cellular and molecular mechanisms underlying such dysfunction, but also the manner in which a primary extrinsic factor for OSAS, obesity, may modify such responses. Given the increasing prevalence of both OSAS and obesity in our society, it is therefore imperative to identify the underlying factors that contribute to the adverse behavioral outcomes associated with the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086662-05
Application #
8287614
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Laposky, Aaron D
Project Start
2008-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$386,100
Indirect Cost
$138,600
Name
University of Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Mutskov, Vesco; Khalyfa, Abdelnaby; Wang, Yang et al. (2015) Early-life physical activity reverses metabolic and Foxo1 epigenetic misregulation induced by gestational sleep disturbance. Am J Physiol Regul Integr Comp Physiol 308:R419-30
Khalyfa, Abdelnaby; Carreras, Alba; Almendros, Isaac et al. (2015) Sex dimorphism in late gestational sleep fragmentation and metabolic dysfunction in offspring mice. Sleep 38:545-57
Tan, Hui-Leng; Kheirandish-Gozal, Leila; Gozal, David (2014) The promise of translational and personalised approaches for paediatric obstructive sleep apnoea: an 'Omics' perspective. Thorax 69:474-80
Khalyfa, Abdelnaby; Gozal, David (2014) Exosomal miRNAs as potential biomarkers of cardiovascular risk in children. J Transl Med 12:162
Almendros, Isaac; Wang, Yang; Gozal, David (2014) The polymorphic and contradictory aspects of intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol 307:L129-40
Kheirandish-Gozal, Leila; Peris, Eduard; Wang, Yang et al. (2014) Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab 99:656-63
Carreras, Alba; Zhang, Shelley X; Peris, Eduard et al. (2014) Chronic sleep fragmentation induces endothelial dysfunction and structural vascular changes in mice. Sleep 37:1817-24
Zhang, S X L; Khalyfa, A; Wang, Y et al. (2014) Sleep fragmentation promotes NADPH oxidase 2-mediated adipose tissue inflammation leading to insulin resistance in mice. Int J Obes (Lond) 38:619-24
Kheirandish-Gozal, Leila; Ghalebandi, Mirfarhad; Salehi, Mansour et al. (2014) Neighbourhood air quality and snoring in school-aged children. Eur Respir J 43:824-32
Kheirandish-Gozal, Leila; Peris, Eduard; Gozal, David (2014) Vitamin D levels and obstructive sleep apnoea in children. Sleep Med 15:459-63

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