The overall goal of this project is to address the postulate that the optimal molecular signature for the common disorder obstructive sleep apnea (OSA) is change in relevant biomarkers during the sleep period. In sleep apnea, events lead to sleep fragmentation and cyclical deoxygenation/reoxygenation. It is proposed that these changes will lead to molecular consequences can be detected by assessing biomarkers in blood. To determine which changes are due to OSA and which to circadian/sleep mechanisms, studies will be done in patients with OSA before and after effective treatment with CPAP and also in controls of similar visceral adiposity without OSA.Multiple assessments of biomarkers will be made before, during and after sleep. Since it is proposed that the magnitude of these dynamic changes across the sleep period will be affected by degree of visceral obesity and be greater in OSA subjects with cardiovascular comorbidities, studies will be done in 4 groups of subjects: lean and obese with and without such morbidities. In assessing biomarkers the primary outcome variables will be: urinary isoprostanes (oxidative stress);plasma TNFa (inflammation); plasma norepinephrine (sympathetic activation);and free fatty acids. Secondary biomarkers will be: IL-6, urinary norepinephrine;urinary normetanephrine;glucose, ICAM, leptin. To complement assessment of circulating biomarkers, an approach utilizing a cellular window will be used. Monocytes will be separated from each blood sample (before, during and after sleep) and RNA extracted. Expression of key genes will be assessed by RT-PCR and microarray studies will be performed in a subset of subjects to assess changes in expression of all genes as a resuft of OSA.A particular focus will be investigating differences between individuals with OSA with and without cardiovascular comorbidities. Three aspects will be evaluated: a) whether individuals with comorbidities have more oxidative stress and inflammatory change for equivalent degrees of OSA than individuals without such comorbidities;b) whether individuals with comorbidities have lower levels of protective mechanisms?melatonin (an anti-oxidant secreted during sleep), IL-10 (anti- inflammatory);c) different gene variants based on a genetic association study using a recently developed CV SNP array. Finally, data will be used to determine whether there is a diagnostic urine and/or blood test for OSA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL094307-05
Application #
8526501
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$282,949
Indirect Cost
$91,605
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Soans, Rajath E; Lim, Diane C; Keenan, Brendan T et al. (2016) Automated Protein Localization of Blood Brain Barrier Vasculature in Brightfield IHC Images. PLoS One 11:e0148411
Magalang, Ulysses J; Arnardottir, Erna S; Chen, Ning-Hung et al. (2016) Agreement in the Scoring of Respiratory Events Among International Sleep Centers for Home Sleep Testing. J Clin Sleep Med 12:71-7
Li, Qing Yun; Berry, Richard B; Goetting, Mark G et al. (2015) Detection of upper airway status and respiratory events by a current generation positive airway pressure device. Sleep 38:597-605
Bjornsdottir, Erla; Keenan, Brendan T; Eysteinsdottir, Bjorg et al. (2015) Quality of life among untreated sleep apnea patients compared with the general population and changes after treatment with positive airway pressure. J Sleep Res 24:328-38
Lim, Diane C; Brady, Daniel C; Po, Pengse et al. (2015) Simulating obstructive sleep apnea patients' oxygenation characteristics into a mouse model of cyclical intermittent hypoxia. J Appl Physiol (1985) 118:544-57
Schwab, Richard J; Kim, Christopher; Bagchi, Sheila et al. (2015) Understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents. Am J Respir Crit Care Med 191:1295-309
Kuna, Samuel T; Shuttleworth, David; Chi, Luqi et al. (2015) Web-Based Access to Positive Airway Pressure Usage with or without an Initial Financial Incentive Improves Treatment Use in Patients with Obstructive Sleep Apnea. Sleep 38:1229-36
Arnardottir, Erna S; Lim, Diane C; Keenan, Brendan T et al. (2015) Effects of obesity on the association between long-term sleep apnea treatment and changes in interleukin-6 levels: the Icelandic Sleep Apnea Cohort. J Sleep Res 24:148-59
Pak, V M; Keenan, B T; Jackson, N et al. (2015) Adhesion molecule increases in sleep apnea: beneficial effect of positive airway pressure and moderation by obesity. Int J Obes (Lond) 39:472-9
Chirinos, Julio A; Gurubhagavatula, Indira; Teff, Karen et al. (2014) CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med 370:2265-75

Showing the most recent 10 out of 34 publications