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: 9123651
• 负责人: Vsevolod Y Polotsky
• 金额: $ 51.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123651
• 关键词: Acute; Address; Adenoviruses; Adipose tissue; Apnea; Blood - brain barrier anatomy; Body Weight; Brain; Bypass; Cardiovascular system; Cell Nucleus; Data; Defect; Development; Diet; Dietary Fats; Disease; Disease model; Eating; Energy Metabolism; Fat-Restricted Diet; Food Energy; Fourth ventricle structure; Future; Gene Transfer; Health; Hormones; Human; Intranasal Administration; Lead; Leptin; Leptin deficiency; Leptin resistance; Mechanics; Modeling; Morbidity - disease rate; Mouse Strains; Mus; New Zealand; Obese Mice; Obesity; Obstruction; Obstructive Sleep Apnea; Pathogenesis; Patients; Permeability; Pharmacotherapy; Pharyngeal structure; Receptor Signaling; Recurrence; Resistance; Rodent; Signal Transduction; Site; Sleep; Sleep Apnea Syndromes; Societies; Source; Staining method; Stains; Suid Herpesvirus 1; Techniques; Tracer; airway obstruction; conventional therapy; db/db mouse; insight; lateral ventricle; leptin receptor; mortality; mouse model; neuromuscular; novel; novel therapeutics; prevent; receptor; response; subcutaneous; translational approach

 DESCRIPTION (provided by applicant): 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.

 描述（由申请人提供）：阻塞性睡眠呼吸暂停是心血管发病率和死亡率的主要来源，常规治疗耐受性差，缺乏有效的药物治疗。由于缺乏对这种疾病的基本认识和转化模型，开发药物治疗的努力受到阻碍。我们将通过解剖睡眠中肥胖者上呼吸道阻塞的潜在致病机制来解决这一差距，总体目标是在特定的小鼠品系中试行新的治疗方法。我们的建议是基于新的发现，即肥胖的瘦素缺乏和瘦素抵抗小鼠有阻塞性睡眠呼吸暂停，瘦素消除睡眠呼吸暂停瘦素缺乏，独立于体重的变化。我们的中心假设是，补充瘦素和克服瘦素抵抗的策略将通过作用于特定的中枢神经系统部位来治疗阻塞性睡眠呼吸暂停。为了解决这一假设，我们将检查具有特定瘦素缺陷的肥胖小鼠：1）具有瘦素缺陷的ob/ob小鼠; 2）具有瘦素ObRb受体缺陷的db/db小鼠; 3）在血脑屏障（BBB）处具有降低的瘦素对CNS的渗透性的新西兰肥胖（NZO）小鼠; 4）具有降低的BBB渗透性和受损的瘦素受体信号传导的C57 BL/6 J饮食诱导的肥胖（DIO）小鼠。最先进的技术将部署在这些小鼠模型，包括脑室内（ICV）和鼻内瘦素管理，和基因转移，以治疗lepti信号转导缺陷。通过对瘦素信号传导和跨神经元示踪剂伪狂犬病病毒（PRV）进行共染色来鉴定瘦素对上呼吸道的作用位点，然后通过使用腺病毒插入ObRb受体来定位于特定的脑核。在SA 1中，我们将研究瘦素替代对ob/ob小鼠睡眠呼吸暂停的影响。我们假设瘦素缺乏导致阻塞性睡眠呼吸暂停，这可以（a）通过侧脑室和第四脑室急性给予瘦素逆转，（B） 通过皮下施用瘦素治疗。在SA 2中，我们将定位和逆转特定脑核团中的瘦素信号传导缺陷，并治疗瘦素抵抗db/db小鼠的阻塞性睡眠呼吸暂停。我们假设缺乏ObRb瘦素受体的db/db小鼠将患有阻塞性睡眠呼吸暂停，这将通过在特定脑核中插入功能性ObRb受体来治疗。在SA 3和4中，我们将通过克服瘦素抵抗来治疗NZO和DIO小鼠的睡眠呼吸暂停。我们推测，血脑屏障对瘦素的通透性降低导致NZO小鼠睡眠呼吸暂停，因此，ICV和鼻内瘦素可以逆转这种情况。在DIO小鼠中，睡眠呼吸暂停是由BBB和ObRb受体信号传导缺陷引起的，并且需要鼻内瘦素和低脂饮食的组合来治疗呼吸暂停。我们的翻译建议将 为通过靶向瘦素信号通路开发治疗睡眠呼吸暂停的新药物奠定基础。