Treatment of Sleep Apnea by Targeting Leptin Signaling

通过靶向瘦素信号传导治疗睡眠呼吸暂停

• 批准号: 9907139
• 负责人: Vsevolod Y Polotsky
• 金额: $ 81.99万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907139
• 关键词: Adherence; Adipocytes; Adult; Affect; Attenuated; Body Weight; Brain; Breathing; Cardiovascular system; Cell Nucleus; Continuous Positive Airway Pressure; Defect; Desire for food; Diet; Disease; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Fatty acid glycerol esters; Female; Fiber; Gender; Goals; Hormones; Human; Hypothalamic structure; Individual; Interneurons; Intervention; Knock-out; Laboratories; Leptin; Magnetic Resonance Imaging; Measurement; Melanocortin 4 Receptor; Metabolic; Morbidity - disease rate; Motor Neurons; Mus; Muscle Tonus; Neurons; Nucleus solitarius; Obese Mice; Obesity; Obstructive Sleep Apnea; Pharmacotherapy; Physiological; Population; Protein Isoforms; Recurrence; Reporting; Research Design; Resistance; Risk Factors; Signal Transduction; Site; Sleep; Sleep Apnea Syndromes; Slice; Synapses; Testing; Therapeutic; Tissues; Work; airway muscle; airway obstruction; db/db mouse; design; designer receptors exclusively activated by designer drugs; effective therapy; experimental study; hypoglossal nucleus; improved; in vivo; leptin receptor; male; metabolic rate; mortality; neuromuscular; novel strategies; optogenetics; patch clamp; selective expression; sex; targeted treatment; therapeutic target; tool

Obstructive sleep apnea (OSA) is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. There is no pharmacotherapy for OSA. There is an urgent need for therapeutics that reverse neuromuscular defects in upper airway function. Our efforts have focused on leptin, an adipocyte-produced hormone, which suppresses appetite, increases metabolic rate, and up-regulates control of breathing. We have previously reported that obese mice develop OSA, which was treated by leptin. Our preliminary results show that (1) leptin receptor (LepRb) deficient db/db mice develop OSA, which was abolished by intracerebroventricular (ICV) leptin after expression of LepRb in the dorsomedial hypothalamus (db/db-LepRb- DMH mice); (2) OSA improved in diet induced obese (DIO) LepRb-Cre mice upon activation of excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) expressed in LepRb+ neurons of the nucleus of the solitary tract (NTS); (3) hypoglossal motoneurons do not express LepRb, but LepRb+ neurons project to the hypoglossal nucleus and photogenetic stimulation of LepRb+ synapses increased hypoglossal motoneuron activity in LepRb-ChR2 mice; (4) LepRb+ neurons in DMH and NTS are melanocortin 4 receptor (MCR4) positive. Our hypothesis is that leptin acts on LepRb+ neurons in DMH and NTS to maintain upper airway patency during sleep. Specific Aim 1 will test the hypothesis that activation of LepRb+ neurons in the DMH alleviates upper airway obstruction and OSA. We propose that (A) selective stimulation of LepRb+ DMH neurons by ICV leptin in db/db-LepRb-DMH mice and by activation of excitatory DREADDs in DIO LepRb-Cre mice will improve upper airway patency and treat OSA; (B) knockout of LepRb+ in DMH neurons by Cre recombinase in DIO LepRb flox/flox mice and inhibition of these neurons in DIO LepRb-Cre mice expressing inhibitory DREADDs will decrease upper airway patency and aggravate OSA; (C) effects of leptin on OSA in db/db-LepRb-DMH mice will be attenuated by MC4R blockers. Specific Aim 2 will examine mechanisms of leptin’s action in the NTS on OSA in vivo and will be designed as SA1 A-C with exception that our interventions will target NTS. Specific Aim 3 will examine synaptic connections between LepRb+ neurons, originating from both the DMH and NTS, that project to and synapse upon hypoglossal motoneurons. We propose that both DMH and NTS LepRb+ neurons connect to hypoglossal motoneurons and that optogenetic stimulation of (A) DMH- and (B) NTS LepRb-channelrhodopsin (ChR2) expressing neurons and fibers activates hypoglossal motoneurons. In SA1-2, we will employ a full arrays of physiological measurements developed in our laboratory including polysomnograms, dynamic MR imaging, and pharyngeal collapsibility measurements in obese male and female mice. In SA3, selective expression of optogenetic tools in targeted LepRb neuronal populations will be employed in combination with patch clamp electrophysiology in brain slices ex vivo. Our proposal will identify leptin-dependent mechanisms which can be targeted for treatment of OSA.

阻塞性睡眠呼吸暂停（OSA）是由上呼吸道肌肉丧失引起的复发性上呼吸道阻塞