Upper Airway Nerve Injury in Apnea: BIP-CHOP-SIRT1 Crosstalk

描述(申请人提供)：阻塞性睡眠呼吸暂停与神经损伤有关，包括运动神经元功能障碍。拟议研究的总体目标是推进间歇性低氧(IH)损伤运动神经元的机制，努力揭示睡眠呼吸暂停治疗方法的新方向。围绕IH损伤的细胞机制，我们发现IH导致舌下和面运动神经元显著的未折叠蛋白反应和细胞凋亡，而三叉神经运动神经元和隐匿性运动神经元则产生抵抗。我们已经确定了敏感运动神经元和抗性运动神经元在IH反应中的几个重要差异。在这项建议中，我们试图测试每种差异作为治疗运动神经元损伤的潜在途径。首先，易感运动神经元表现出内质网(ER)感受器PERK的激活，以响应IH。当内质网的主调节伴侣Bip从PERK释放到伴侣未折叠蛋白时，PERK被激活。在目标1中，我们将测试BiP在保护运动神经元免受IH损伤中所起的作用。易感运动神经元积聚一种促凋亡蛋白CHOP。因此，我们怀疑易感运动神经元中CHOP的降解受损是导致它们死亡的原因(目标2)。免疫球蛋白对其他细胞器和细胞突起造成严重损伤。其中哪些是内质网损伤的继发性损伤，哪些是原发损伤，将进行探讨。SIRT1可能在应对IH的代谢挑战方面发挥更全球性的作用(目标3)。这里，将再次确定BIP、CHOP和SIRT1路径之间的串扰。在小鼠中确定了上呼吸道运动神经元对IH的不同易感性，并确定了ER和氧化应激损伤途径中的关键介质后，我们接下来将在死后的人类上呼吸道运动神经元中检查这些机制。这项工作旨在推进阻塞性睡眠呼吸暂停患者神经损伤的新疗法。 公共卫生相关性：阻塞性睡眠呼吸暂停是儿童和成人的常见疾病，在成人中，睡眠呼吸暂停与周围神经和脑损伤有关。使用睡眠呼吸暂停氧合模式的小鼠模型，我们已经确定了对支配上呼吸道的神经元的严重损伤。拟议的研究旨在确定预防和/或逆转损伤的治疗的新途径。

DESCRIPTION (provided by applicant): Obstructive sleep apnea is associated with neural injury, including motoneuronal dysfunction. The overall goal of the proposed studies is to advance mechanisms by which intermittent hypoxia (IH) injures motoneurons in an effort to unveil novel directions for development of therapies for sleep apnea. Focusing on cellular mechanisms of IH injury, we have found that IH results in a marked unfolded protein response and apoptosis in hypoglossal and facial motoneurons, while motor trigeminal and occulomotor neurons confer resistance. We have identified several important differences in the IH response between susceptible and resistant motoneurons. In this proposal, we seek to test each difference as a potential avenue for treating motoneuronal injury. First, susceptible motoneurons show activation of an endoplasmic reticulum (ER) sensor, PERK, in response to IH. PERK is activated when BiP, the master regulator chaperone of the ER, is released from PERK to chaperone unfolded proteins. In Aim 1, we will test the role BiP plays in protecting motoneurons from IH injury. IH susceptible motoneurons accumulate a pro-apoptotic protein CHOP. Thus we suspect impaired degradation of CHOP in susceptible motoneurons contributes to their demise (Aim 2). IH cause significant injury to other organelles and cellular processes. Which of these are secondary to ER injury or which are primary will be explored. SIRT1 may play a more global role in responding to the metabolic challenges of IH (Aim 3). Here again, crosstalk between BiP, CHOP and SIRT1 pathways will be determined. Having identified in mice a differential IH susceptibility across upper airway motoneurons and having identified key mediators in the ER and oxidative stress injury pathways, we will next examine these mechanisms in post-mortem human upper airway motoneurons. This work is designed to advance novel therapeutics for nerve injury in obstructive sleep apnea. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea is a common disorder in children as well as in adults, and in adults, sleep apnea is associated with peripheral nerve and brain injury. Using a mouse model of the sleep apnea oxygenation patterns we have identified a significant injury to the neurons that innervate the upper airway. The proposed studies are designed to identify novel pathways for therapies to prevent and/or reverse the injuries.