Sleep Apnea: Upper Airway Nerve Injury

描述（由申请人提供）：阻塞性睡眠呼吸暂停的状态依赖性意味着该疾病可以通过药物治疗来对抗与睡眠相关的扩张神经兴奋丧失。许多舌下运动神经元兴奋性受体亚型已被确定。然而，最近，我们观察到长期间歇性缺氧（LTIH），模拟中重度睡眠呼吸暂停的氧合模式，导致舌下神经活动对局部应用血清素和谷氨酸激动剂的反应减少。但我们现在必须确定是否其他上呼吸道扩张神经同样受到LTIH的影响（Aim 1A），然后开始引出LTIH运动神经损伤的机制。在我们的初步研究中，我们发现运动核中蛋白质的羰基化增加。在神经元蛋白上形成氧化晚期糖基化终产物（cmage）是一种可能在运动神经元中发生和积累并损害功能的羰基化反应。接下来，我们将确定ltih -羰基AGE积累是否与多个上呼吸道运动神经元池的兴奋性神经化学反应受损同时发生（Aim IB）。AGE的重要性必须通过预防LTIH中AGE的积累和显示神经反应性的改善来证实（Aim 1C）。先前的工作和我们的初步结果表明，CMLAGE在AGE受体上激活小胶质细胞导致NAD(P)H氧化酶活化；这反过来又增加细胞外超氧化物，氧化运动神经元和小胶质细胞中的AGE，导致功能受损，释放更多CML-AGE，从而触发进一步的NAD(P)H氧化酶活化。我们将通过一系列互补的NAD(P)H氧化酶活性降低的药理学和转基因模型来证实NAD(P)H氧化酶的重要性，显示LTIH后神经功能的保存，并减少氧化损伤，包括羰基AGE的产生（Aim2）。体内研究应辅以体外研究，以确定小胶质细胞在LTIH神经损伤和AGE生成中的作用（目的3）。人类AGE的另一个常见来源是慢性高血糖症，如糖尿病。糖尿病存在于许多睡眠呼吸暂停的成年人中。我们认为糖尿病会增加AGE的产生，因此，睡眠呼吸暂停患者的LTIH神经损伤的风险更大。在最后的目的中，我们将使用小鼠和大鼠糖尿病模型来确定慢性高血糖是否会加重LTIH诱导的AGE积累和LTIH神经损伤，以及仔细控制血糖是否可以预防LTIH的损伤（目的4）。总的来说，拟议的研究将揭示阻塞性睡眠呼吸暂停神经损伤的重要机制，并应揭示糖尿病是睡眠呼吸暂停神经损伤的危险因素。

DESCRIPTION (provided by applicant): The state-dependency in obstructive sleep apnea implies that the disorder could be treated with pharmacotherapies countering the sleep-related loss of dilator nerve excitation. Many of the hypoglossal motoneuron excitatory receptor subtypes have been identified. Recently, however, we observed that long-term intermittent hypoxia (LTIH), modeling oxygenation patterns in moderate-severe sleep apnea, results in reduced excitation of hypoglossal nerve activity in response to locally applied serotonin and glutamate agonists. But we must now determine if other upper airway dilator nerves are equally affected by LTIH (Aim 1A) and then begin to elicit the mechanisms underlying LTIH motor nerve impairments. In our preliminary studies, we have found carbonylation of proteins increased in motor nuclei. A carbonylation reaction likely to occur and accumulate in motoneurons and impair function is the formation of oxidized advanced glycation end products (CMLAGE) on neuronal proteins. We will next determine if LTIH-carbonyl AGE accumulation occurs in parallel with impaired excitatory neurochemical responses in multiple upper airway motoneuronal pools (Aim IB). The importance of AGE must be substantiated by preventing AGE accumulation in LTIH and showing improved nerve responsiveness (Aim 1C). Previous work and our preliminary results suggest microglia activation by CMLAGE at the AGE receptor resulting in NAD(P)H oxidase activation; this in turn increases extracellular superoxide that oxidizes AGE in motoneurons and microglia resulting in impaired function and release of more CML-AGE to trigger further NAD(P)H oxidase activation. We will substantiate the importance of NAD(P)H oxidase with a series of complementary pharmacological and transgenic models of reduced NAD(P)H oxidase activity, showing preservation of nerve function following LTIH, and reduced oxidative injury including carbonyl AGE production (Aim2). In vivo studies should be complemented with in vitro studies to determine the microglial role in LTIH nerve injury and AGE production (Aim 3). Another common source of AGE in humans is chronic hyperglycemia, as in diabetes. Diabetes is present in many adults with sleep apnea. We believe diabetes increases AGE production and thus, places persons with sleep apnea at greater risk of LTIH nerve injury. In the final Aim, we will use mouse and rat models of diabetes to determine if chronic hyperglycemia worsens LTIH induced AGE accumulation and LTIH nerve injury, and if careful glucose control may prevent the injuries from LTIH (Aim 4). Collectively, the proposed studies will unveil important mechanisms of neuronal injury in obstructive sleep apnea and should reveal diabetes is a risk factor for this neural injury in sleep apnea.