Treatment of sleep apnea by targeting leptin signaling

 描述(申请人提供)：阻塞性睡眠呼吸暂停是心血管疾病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翻译模型，开发药物疗法的努力一直受到阻碍。我们将通过剖析睡眠期间肥胖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验新的治疗方法。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的小鼠患有阻塞性睡眠呼吸暂停，瘦素缺乏时瘦素可以消除睡眠呼吸暂停，与体重的变化无关。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在特定中枢神经系统部位的作用来治疗阻塞性睡眠呼吸暂停。为了解决这一假设，我们将研究具有特定瘦素缺陷的肥胖小鼠：1)ob/ob小鼠瘦素缺乏；2)db/db小鼠瘦素ObRb受体缺乏；3)新西兰肥胖(NZO)小鼠血脑屏障(BBB)对中枢神经系统的瘦素通透性降低；4)C57BL/6J饮食诱导的肥胖(DIO)小鼠血脑屏障通透性降低，瘦素受体信号转导受损。最先进的技术将被用于治疗这些小鼠模型中的瘦素信号缺陷，包括脑室(ICV)和鼻腔内给药，以及基因转移。瘦素在上呼吸道的作用部位将通过瘦素信号和跨神经元示踪伪狂犬病病毒(PRV)的共同染色来确定，然后通过使用腺病毒插入ObRb受体来定位到特定的脑核。在SA1中，我们将检查瘦素替代对肥胖/肥胖小鼠睡眠呼吸暂停的影响。我们假设，瘦素缺乏会导致阻塞性睡眠呼吸暂停，这可以(A)通过向侧脑室和第四脑室急性注射瘦素来逆转，并且可以(B) 皮下注射瘦素治疗。在SA2中，我们将定位和逆转特定脑核中的瘦素信号缺陷，并治疗瘦素抵抗的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小鼠将会患有阻塞性睡眠呼吸暂停，这将通过在特定脑核插入功能性ObRb受体来治疗。在SA3和SA4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。我们假设瘦素的血脑屏障通透性降低会导致NZO小鼠的睡眠呼吸暂停，因此，脑室和鼻腔内注射瘦素将逆转这一现象。在DIO小鼠中，睡眠呼吸暂停是由BBB和ObRb受体信号缺陷引起的，需要鼻内注射瘦素和低脂饮食来治疗呼吸暂停。我们的翻译提案将 通过靶向瘦素信号，为开发治疗睡眠呼吸暂停的新型药物疗法奠定基础。

 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.