Obstructive sleep apnea is a common disorder whose prevalence is linked to an epidemic of obesity in Western society. Sleep apnea is due to recurrent episodes of upper airway obstruction during sleep that are caused by elevations in upper airway collapsibility during sleep. Current evidence indicates that anatomic alterations and disturbances in upper airway neuromuscular control play key roles in the pathogenesis of obstructive sleep apnea. Obesity and particularly central adiposity are potent risk factors for sleep apnea. Our primary hypothesis is that metabolic and inflammatory dysregulation in obesity produce specific defects in upper airway mechanical and neuromuscular control during sleep. To address this hypothesis, human and murine models will be probed to characterize the mechanisms of upper airway dysfunction during sleep in obesity. Dramatic surgical weight loss and specific nocturnal interventions will be implemented to elucidate specific physiologic, metabolic and inflammatory mechanisms causing upper airway dysfunction during sleep (SA 1 &2). Complementary murine experiments are proposed to establish specific adipocytokines and metabolic pathways in the pathogenesis of upper airway obstruction during sleep (SA3). An inter-disciplinary team will leverage scientific and institutional resources in this project to: (1) define distinct physiologic, metabolic and inflammatory mediators of sleep apnea susceptibility, and (2) lay the groundwork for targeting novel biomarkers and pathways for diagnostic and therapeutic purposes.

Public Health Relevance

Obstructive sleep apnea is a common disorder associated with substantial morbidity and mortality whose prevalence is linked to an epidemic of obesity in Western society. This proposal addresses the underlying physiologic, metabolic and inflammatory causes of sleep apnea in obesity. It promises to uncover new strategies for early diagnosis and treatment of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050381-18
Application #
8318193
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
1994-04-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
18
Fiscal Year
2012
Total Cost
$580,975
Indirect Cost
$226,722
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Kobayashi, Masato; Ayuse, Takao; Hoshino, Yuko et al. (2011) Effect of head elevation on passive upper airway collapsibility in normal subjects during propofol anesthesia. Anesthesiology 115:273-81
Ayuse, Takao; Hoshino, Yuko; Kurata, Shinji et al. (2009) The effect of gender on compensatory neuromuscular response to upper airway obstruction in normal subjects under midazolam general anesthesia. Anesth Analg 109:1209-18
Savransky, Vladimir; Jun, Jonathan; Li, Jianguo et al. (2008) Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase. Circ Res 103:1173-80