Obstructive sleep apnea is a major source of cardiovascular morbidity and mortality for which conventional treatment is poorly tolerated and effective pharmacotherapy is lacking. Efforts to develop pharmacotherapy have been hindered by a lack of fundamental insight and translational models of this disorder. We will address this gap by dissecting underlying pathogenic mechanisms of upper airway obstruction in obesity during sleep with the overall objective of piloting novel therapy in specific murine strains. Our proposal is predicated on novel findings that obese leptin deficient and leptin resistant mice have obstructive sleep apnea and that leptin abolishes sleep apnea in leptin deficiency, independent of changes in body weight. Our central hypothesis is that strategies to replete leptin and overcome leptin resistance will treat obstructive sleep apnea through actions at specific CNS sites. To address this hypothesis, we will examine obese mice with specific leptin defects: 1) ob/ob mice with leptin deficiency; 2) db/db mice with leptin ObRb receptor deficiency; 3) New Zealand obese (NZO) mice with reduced leptin permeability to the CNS at the blood brain barrier (BBB); 4) C57BL/6J diet-induced obese (DIO) mice with reduced BBB permeability and impaired leptin receptor signaling. State of the art techniques will be deployed to treat lepti signaling defects in these mouse models, including intracerebroventricular (ICV) and intranasal leptin administration, and gene transfer. Sites of leptin's effects on the upper airway will be identified by co- staining for leptin signaling and transneuronal tracer Pseudorabies virus (PRV) and then localized to specific brain nuclei by insertion of the ObRb receptor using an adenovirus. In SA1, we will examine effects of leptin replacement on sleep apnea in ob/ob mice. We hypothesize that leptin deficiency causes obstructive sleep apnea, which can be (a) reversed by acute administration of leptin ICV to the lateral and fourth ventricles, and can be (b) treated by subcutaneous leptin administration. In SA2, we will localize and reverse leptin signaling defects in specific brain nuclei and treat obstructive sleep apnea in leptin-resistant db/db mice. We hypothesize that db/db mice lacking the ObRb leptin receptor will have obstructive sleep apnea that will be treated by insertion of functional ObRb receptors in specific brain nuclei. In SA3 and 4, we will treat sleep apnea in NZO and DIO mice by overcoming leptin resistance. We hypothesize that reduced BBB permeability for leptin causes sleep apnea in NZO mice, and, therefore it will be reversed by ICV and intranasal leptin. In DIO mice, sleep apnea is caused by both the BBB and ObRb receptor signaling defects and a combination of intranasal leptin and low fat diet will be required to treat apnea. Our translational proposal will lay the groundwork for developing novel pharmacotherapy for sleep apnea by targeting leptin signaling.

Public Health Relevance

This proposal will lay the groundwork for the development of novel pharmacotherapy for patients with obstructive sleep apnea, a major source of cardiovascular morbidity and mortality in Western societies. We will utilize obese mouse strains to model leptin deficiency and leptin resistance in humans, and will target specific defects of leptin signaling, which are common in human obesity. Capitalizing on novel translational approaches, the proposal will (a) implicate leptin deficiency and leptin resistance in the pathogenesis of sleep apnea, and (b) pilot novel therapies to overcome these leptin signaling defects for the future use in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128970-02
Application #
9123651
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Brown, Marishka
Project Start
2015-08-10
Project End
2019-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Fleury Curado, Thomaz A; Pho, Huy; Dergacheva, Olga et al. (2018) Silencing of Hypoglossal Motoneurons Leads to Sleep Disordered Breathing in Lean Mice. Front Neurol 9:962
Fleury Curado, Thomaz; Berger, Slava; Polotsky, Vsevolod Y (2018) Pharmacotherapy of Obstructive Sleep Apnea: Is Salvation Just Around a Corner? Am J Respir Crit Care Med :
Pham, Luu V; Schwartz, Alan R; Polotsky, Vsevolod Y (2018) Integrating loop gain into the understanding of obstructive sleep apnoea mechanisms. J Physiol 596:3819-3820
Fleury Curado, Thomaz; Pho, Huy; Berger, Slava et al. (2018) Sleep-disordered breathing in C57BL/6J mice with diet-induced obesity. Sleep 41:
Holingue, Calliope; Wennberg, Alexandra; Berger, Slava et al. (2018) Disturbed sleep and diabetes: A potential nexus of dementia risk. Metabolism 84:85-93
Berger, Slava; Pho, Huy; Fleury-Curado, Thomaz et al. (2018) Intranasal Leptin Relieves Sleep Disordered Breathing in Mice with Diet Induced Obesity. Am J Respir Crit Care Med :
Berger, Slava; Polotsky, Vsevolod Y (2018) Leptin and Leptin Resistance in the Pathogenesis of Obstructive Sleep Apnea: A Possible Link to Oxidative Stress and Cardiovascular Complications. Oxid Med Cell Longev 2018:5137947
Drager, Luciano F; Tavoni, Thauany M; Silva, Vanessa M et al. (2018) Obstructive sleep apnea and effects of continuous positive airway pressure on triglyceride-rich lipoprotein metabolism. J Lipid Res 59:1027-1033
Fleury Curado, Thomaz; Oliven, Arie; Sennes, Luiz U et al. (2018) Neurostimulation Treatment of OSA. Chest 154:1435-1447
Pham, Luu V; Miele, Catherine H; Schwartz, Noah G et al. (2017) Cardiometabolic correlates of sleep disordered breathing in Andean highlanders. Eur Respir J 49:

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