Basic Research

 

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.

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.

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

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

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.

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.

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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