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: 7790100
• 负责人: SIGRID C VEASEY
• 金额: $ 45.43万
• 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/7790100
• 关键词: Adult; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apnea; Apoptotic; Brain Injuries; Cell physiology; Child; Deacetylase; Development; Disease; Docking; Endoplasmic Reticulum; Enzyme Inhibition; Face; Figs - dietary; 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 Nerves; 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。本研究的总体目标是研究间歇性缺氧（IH）损伤运动神经元的机制，为睡眠呼吸暂停治疗的发展开辟新的方向。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的显著未折叠蛋白反应和凋亡，而三叉运动神经元和眼运动神经元赋予抵抗。我们已经确定了易感和耐药运动神经元在IH反应中的几个重要差异。在这个建议中，我们试图测试每个差异作为治疗运动神经损伤的潜在途径。首先，易感运动神经元表现出内质网（ER）传感器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Aim 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的受损降解有助于它们的死亡（目的2）。IH对其他细胞器和细胞过程造成严重损伤。其中哪些是继发于ER损伤，哪些是原发性损伤，我们将进行探讨。SIRT1可能在应对IH的代谢挑战中发挥更全面的作用（Aim 3）。在这里，BiP， CHOP和SIRT1通路之间的串扰将被确定。在小鼠上气道运动神经元中发现了不同的IH易感性，并确定了内质网和氧化应激损伤途径中的关键介质，接下来，我们将在死后的人类上气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。