BASIC RESEARCH

 

Highlights

Intranasal Leptin for Opiod Induced Respiratory Depression

Obesity increases the risk of opiod-induced respiratory depression(OIRD), especially during sleep. We used Leptin, a powerful respiratory stimulant, as an intranasal pharmacotherapy to prevent OIRD without interference with analgesia.

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DREADD Approach to Treatment of Sleep Disordered Breathing

Representative PET-Scan images (A) in AAV9-hSyn-GFP treated mice (n=5) and (B) in AAV-hSyn-DIO-hM3D(Gq)-mCherry treated mice (n=7). Note the robust increase in tongue metabolic activity (white arrow) in mice treated with -DREADD. 2-deoxy-2-[18F]fluoroDglucose (FDG) uptake in Standardized Uptake Values (SUVs) in individual mice infected with (C) GFP or (D) DREADD. Bars reflect median values. *, p < 0.001. 

Figure from: Fleury Curado et al. Am J Respir Crit Care Med. 2020 Jul 16. PMID: 32673075.

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Chemogenetics for Targeted  Obstructive Sleep Apnea Therapy

Sleep apnea is related to a defect in neuromuscular control of the pharynx.  Our laboratory has pioneered a technique to augment airway patency by deploying Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in the hypoglossal motor neuron of mice.  We are now refining our technique to improve the specificity of DREADD delivery, using Cre-Lox technology and retrograde viral transfection.  Ultimately, this project may allow for precise activation of tongue muscles for the neurostimulation treatment of sleep apnea.

Figure from:  Fleury Curado et al.  Sci Rep. 2017 Mar 10;7:44392

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Leptin and Control of Breathing

Leptin is a hormone produced by adipose tissue that regulates appetite and metabolism.  Leptin-deficient (ob/ob) mice develop obesity, sleep apnea, and hypoventilation.   We found and that replacing leptin improves upper airway function, and that leptin binds receptors in the carotid body to  stimulate breathing and the hypoxic ventilatory response.

We also showed that delivering intranasal leptin (bypassing the blood-brain barrier) significantly improves OSA.

We are also using viral transfection techniques to manipulate leptin receptor expression in the carotid body, and examining chemo-reflexes and blood pressure responses to leptin infusion.

Figure from: Yao et al.  Sleep. 2016 May 1; 39(5): 1097–1106

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Carotid body Leptin Signaling

Leptin reduces food intake and increases metabolic rate but may be a “double-edged sword” since it can also activate the sympathetic nervous system and increase blood pressure.  We discovered that leptin binds to receptors on the carotid body and in turn elevates blood pressure and stimulates breathing.  Now, we are using viral transfection to manipulate leptin receptor expression in the carotid body to explore novel therapy for this pathway.

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Asthma, high fat diet, and particulate matter

Obesity and/or high fat diet can aggravate airway hyper-reactivity and asthma.  We showed that a high fat diet induces airway hyper-responsiveness in mice in association with lung inflammation (IL-1β levels). 

Furthermore, air pollution with particulate matter can induce or exacerbate asthma.  We are investigating the interaction of particulate matter with diet on airway physiology and inflammation in mice.  This project may reveal interactions between asthma, nutrition, and air quality and provide possible targets for intervention.

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Leptin and OSA

Leptin-deficient (ob/ob) mice demonstrate defects in upper airway structural and neuromuscular control. Leptin administration reversed these defects and stabilized pharyngeal patency and increased drive to both the upper airway and diaphragm during sleep.

Figure from: Pho et al. J Appl Physiol (1985). 2016 Jan 1;120(1):78-86. doi: 10.1152/japplphysiol.00494.2015. Epub 2015 Oct 15. PMID: 26472867; PMCID: PMC4698442.

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Misty Slope

Active Projects

Treatment of sleep apnea by targeting leptin signaling     08/10/2015 – 03/31/2024           

R01 HL128970

PI: Polotsky, Vsevolod

The overall goal of this proposal is to identify specific CNS sites where leptin acts to control upper airway patency during sleep

Leptin signaling in the carotid body: mechanisms and consequences     07/01/2016 – 03/31/2025           

R01 HL133100

PIs: Polotsky, Vsevolod and Sham, James

The overall goal of this project is examine pathways by which leptin signals in the carotid body in obesity exacerbating sleep apnea and causing hypertension.


Chemogenetic Approach to Treat Obstructive Sleep Apnea     08/04/2017 – 06/30/2022             

R01 HL138932 

PI: Polotsky, Vsevolod

The proposal will examine the impact of specific hypoglossal motor neurons innervating lingual protrudor and retractor muscles on pharyngeal patency and obstructive sleep apnea.


Intranasal Leptin as a Novel Treatment of Opioid-induced Respiratory Depression     09/20/2020 – 08/31/2022 

R61 HL156240     

PI: Polotsky, Vsevolod (20%)

We propose that intranasal route will deliver leptin to the brain where it will prevent opioid induced suppression of breathing and obstructive sleep apnea without opioid withdrawal or affecting analgesia. We predict that intranasal leptin will be indicated in high-risk populations: patients with obstructive sleep apnea requiring opioid analgesia and in chronic opioid users requiring high dose opioids for pain control.


Targeting Leptin Pathway to Treat Opioid-Induced Respiratory Depression     11/15/2020 – 10/31/2021        

U18 DA052301-01

PI: Polotsky, Vsevolod   

 We propose that intranasal leptin will synergize with naloxone treat acute opioid-induced respiratory depression and upper airway obstruction by antagonizing inhibiting effects of opioids on hypoglossal motoneurons                                       


Mechanisms of Leptin-induced Hypertension     04/01/2019 – 03/31/2022        

American Heart Association Career Development Award 19CDA34700025

PI: Shin, Mi-Kyung

The proposal is focused on the role of carotid body in the pathogenesis of leptin-induced hypertension in obesity


Chemogenetic Approach to Treat Obstructive Sleep Apnea     04/01/2019 – 03/31/2022

American Heart Association Career Development Award 19CDA34660245

PI: Fleury Curado, Thomaz

The proposal is focused on the role of chemogenetics in reversing upper airway obstruction during sleep in a mouse model


Role of leptin-TRPM7 signaling in carotid bodies in the pathogenesis of sleep-disordered breathing in obesity     04/01/2021 – 03/31/2023

American Heart Association Postdoctoral Fellowship Award 828142                      

PI: Kim, Lenise

This project will examine the role of TRPM7 signaling in the carotid body in the pathogenesis of sleep disordered breathing