This Program Project Grant (PPG) is focused on the common problem of obstructive sleep apnea (OSA) and its relationship with obesity. Patients with OSA not only develop excessive sleepiness, but are at increased risk for hypertension, insulin resistance and cardiovascular events. Obesity is the major risk factor for OSA. Patients with OSA have oxidative stress, sympathetic activation, and increased inflammatory state that are independent of obesity. Since obesity is also postulated to produce identical effects, and OSA and obesity common coexist, it is important to consider the relative role of these two pathogenetic processes. The program of research has three projects and five cores. Project 01 (PL, Dr. R. Schwab) is directed at the question as to why obesity leads to OSA. It is proposed that the major pathogenetic mechanism is fat infiltration of tongue and other upper airway structures that increase their size, thereby reducing airway size and affecting the function of muscle. This will be addressed in a human case-control study, in a longidutinal study of individuals loosing weight after bariatric surgery, and in rat models of obesity. The project will use novel, state-of-the-art MRI techniques to assess fat in tongue and other structures. In Project 02 (PL, Dr. S. Kuna), a multidisciplinary team has been assembled to address whether the presence of obesity attenuates benefits of treatment of OSA on insulin resistance, hypertension and CV function, since obesity in the absence of OSA produces these effects. The study is powered to separately assess treatment effects in individuals with low and higher amounts of visceral fat. The study also assesses changes in biomarkers of the relevant processes-oxidation, sympathetic activity, proflammatory cytokines, adhesion molecules and free fatty acids. Controls without OSA are included to assess whether OSA leads to irreversible changes in clinical end-points. Project 03 (PL, Dr. A. Pack) proposes to assess temporal changes in biomarkers during sleep in subjects with OSA both before and after effective treatment with CPAP. The concept that movitates this project is that studying change in these processes across the sleep period provides a molecular signature of OSA. Studies are done in obese and lean individuals with OSA with and without cardiovascular consequences and in controls. It is argued that obesity will alterthe nature of the biomarker response to OSA, and individuals with OSA who develop comorbidities will have greater oxidative stress and inflammatory state than those who do not. The PPG is supported by five cores (A: Administrative;B: Sleep Study and Recruitment: C: Imaging;D: Biomarker;and E: Biostatistical and Data Management). Thus, this PPG is focused on a common clinical problem. The program will lead to defining who with OSA benefits from therapy and the magnitude of benefit for different end-points. It will lead to a new molecular signature of OSA that could transform the practice of medicine in this area in a new, cost-effective way.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Twery, Michael
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Eysteinsdottir, Bjorg; Gislason, Thorarinn; Pack, Allan I et al. (2017) Insomnia complaints in lean patients with obstructive sleep apnea negatively affect positive airway pressure treatment adherence. J Sleep Res 26:159-165
Jain, Snigdha; Gurubhagavatula, Indira; Townsend, Raymond et al. (2017) Effect of CPAP, Weight Loss, or CPAP Plus Weight Loss on Central Hemodynamics and Arterial Stiffness. Hypertension 70:1283-1290
Kim, Jinyoung; Pack, Allan I; Riegel, Barbara J et al. (2017) Objective snoring time and carotid intima-media thickness in non-apneic female snorers. J Sleep Res 26:147-150
Schwab, Richard J; Leinwand, Sarah E; Bearn, Cary B et al. (2017) Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest 152:330-342
Horner, Richard L; Grace, Kevin P; Wellman, Andrew (2017) A resource of potential drug targets and strategic decision-making for obstructive sleep apnoea pharmacotherapy. Respirology 22:861-873
Lyons, M Melanie; Keenan, Brendan T; Li, Junxin et al. (2017) Symptomless Multi-Variable Apnea Prediction Index Assesses Obstructive Sleep Apnea Risk and Adverse Outcomes in Elective Surgery. Sleep 40:
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
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
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
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

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