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

呼吸暂停时的上气道神经损伤：BIP-CHOP-SIRT1 串扰

• 批准号: 8010891
• 负责人: SIGRID C VEASEY
• 金额: $ 39.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010891
• 关键词: Adult; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apnea; Apoptotic; Autopsy; Brain Injuries; Cell physiology; Child; Deacetylase; Development; Disease; Docking; Endoplasmic Reticulum; Enzyme Inhibition; Face; Functional disorder; Genes; Genetic Transcription; Goals; Histone Deacetylase; Human; Hypoglossal nerve structure; Hypoxia; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Mediator of activation protein; Metabolic; Modeling; Molecular; Molecular Chaperones; Motor; Motor Neurons; Mus; Nerve; Neuronal Injury; Neurons; Nuclear; Obstructive Sleep Apnea; Oranges; Organelles; Oxidative Stress; PAWR protein; Pathway interactions; Pattern; Peripheral nerve injury; Pharmacotherapy; Play; Population; Predisposition; Production; Proteins; Recovery; Research Design; Resistance; Rest; Role; Secondary to; Sleep Apnea Syndromes; Superoxide Dismutase; Testing; Therapeutic; Transgenic Organisms; Translations; Trigeminal System; Work; antioxidant therapy; design; endoplasmic reticulum stress; gene therapy; human tissue; improved; injured; mimetics; mouse model; nerve injury; neurobehavioral; novel; novel therapeutic intervention; novel therapeutics; oxidation; prevent; pro-apoptotic protein; protein folding; protein misfolding; public health relevance; response; sensor; suicidal; therapy development

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.

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疗法开发的新方向。关注 IH 损伤的细胞机制，我们发现 IH 导致舌下和面部运动神经元显着的未折叠蛋白反应和细胞凋亡，而运动三叉神经和动眼神经元则产生抵抗。我们已经确定了易感运动神经元和耐药运动神经元之间 IH 反应的几个重要差异。在本提案中，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，易受影响的运动神经元响应 IH 显示内质网 (ER) 传感器 PERK 的激活。当 ER 的主调节分子伴侣 BiP 从 PERK 释放到分子伴侣未折叠蛋白时，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 损伤中的作用。 IH 易感运动神经元积聚促凋亡蛋白 CHOP。因此，我们怀疑易感运动神经元中 CHOP 降解受损导致其死亡（目标 2）。 IH 对其他细胞器和细胞过程造成严重损伤。将探讨哪些是继发于内质网损伤的，哪些是原发性的。 SIRT1 可能在应对 IH 代谢挑战方面发挥更全面的作用（目标 3）。此处将再次确定 BiP、CHOP 和 SIRT1 通路之间的串扰。在小鼠中确定了上气道运动神经元之间的 IH 易感性差异，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人类上气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，我们发现了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/或逆转损伤的新疗法途径。