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

描述（由申请人提供）：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缺氧（IH）损伤运动神经元的机制，努力揭示睡眠呼吸暂停治疗发展的新方向。专注于IH损伤的细胞机制，我们已经发现，IH的结果在一个显着的未折叠的蛋白质反应和细胞凋亡的舌下神经和面部运动神经元，而运动三叉神经和occulminal神经元赋予阻力。我们已经确定了几个重要的差异，在IH敏感和耐药运动神经元之间的反应。在这个建议中，我们试图测试每个差异作为治疗运动神经元损伤的潜在途径。首先，易感运动神经元显示激活内质网（ER）传感器，PERK，响应IH。当ER的主调节分子伴侣BiP从PERK释放到伴侣未折叠蛋白质时，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损伤中的作用。IH易感运动神经元积累促凋亡蛋白CHOP。因此，我们怀疑易感运动神经元中CHOP的降解受损有助于其死亡（目的2）。IH对其他细胞器和细胞过程造成显著损伤。将探讨其中哪些是ER损伤的继发性，哪些是原发性。SIRT1可能在应对IH的代谢挑战方面发挥更全面的作用（目的3）。这里再次确定BiP、CHOP和SIRT1通路之间的串扰。在小鼠上呼吸道运动神经元中鉴定了不同的IH易感性，并鉴定了ER和氧化应激损伤途径中的关键介质，我们接下来将在死后人类上呼吸道运动神经元中研究这些机制。这项工作旨在推进阻塞性睡眠呼吸暂停神经损伤的新疗法。

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.