Integrative Consequences of Intermittent Hypoxia

项目概要-总体 此申请是为一个新的计划项目赠款题为“间歇性缺氧的综合后果”。 慢性间歇性缺氧（CIH）是睡眠呼吸暂停的霍尔标记表现， 这种疾病仅在美国就影响了数百万人。睡眠呼吸暂停患者和啮齿动物暴露于 IH表现出过度活跃的交感神经系统，这已经牵连到许多病理 睡眠呼吸暂停引起的拟议方案的首要目标是确定CIH如何导致 交感神经激活并确定其后果。该方案的具体目标是：目标1- 确定IH导致交感神经激活的神经机制。外周和中枢 与CIH引起的交感神经激活相关的神经机制将在项目1中确定， 2.目的2-CIH引起的交感神经激活的后果，将在项目3中通过确定 交感神经激活对CIH激活内皮细胞的作用。目的3-阐明表观遗传 CIH诱导的交感神经激活的潜在机制，这将是项目4的重点。所有四 项目将由一个行政核心和一个科学核心支持。该计划的研究利用 暴露于IH范例的啮齿动物模仿血液O2饱和度曲线，类似于 睡眠呼吸暂停以及表现出自然睡眠呼吸暂停的小鼠。概念创新-细胞和分子 本项目中提出的CIH交感神经激活机制是新颖的， 除睡眠呼吸暂停外，还可适用于其他心肺疾病。重大技术创新 包括评估自然发生的IH实验啮齿动物模型中发现的重要性， 睡眠呼吸暂停小鼠模型。该项目的研究人员已经证明了在细胞， 分子和系统水平的调查，并有良好的合作记录。完成 该计划预计将为开发新的治疗策略提供重要的见解，以减轻 与IH相关的自主共病，这是睡眠呼吸暂停的主要表现。因为 通过项目之间紧密的主题联系，从整个计划中获得的全部知识将真正 大于每个项目的总和。

Project Summary- Overall This application is for a new Program Project Grant entitled "Integrative consequences of intermittent hypoxia”. Chronic intermittent Hypoxia (CIH) is a hall mark manifestation of sleep apnea, a highly prevalent respiratory disease affecting several million people in the USA alone. Patients with sleep apnea and rodents exposed to IH exhibit hyperactive sympathetic nervous system, which has been implicated in many of the pathologies caused by sleep apnea. The overarching goal of the proposed Program is to determine how CIH leads to sympathetic nerve activation and determine its consequences. Specific Aims of the program are: AIM 1- Determines the neural mechanism(s) contributing to sympathetic nerve activation by IH. Peripheral and central neural mechanisms associated with sympathetic activation by CIH which will be determined in Projects 1 and 2. AIM 2- Consequences of sympathetic activation by CIH, which will be addressed in Project 3 by determining the contribution of sympathetic activation to endothelial cell activation by CIH. AIM 3- Elucidates the epigenetic mechanisms underlying CIH-induced sympathetic nerve activation, which will be the focus of Project 4. All four Projects will be supported by an Administrative Core and a Scientific Core. Studies in this program utilize rodents exposed to an IH paradigm mimicking the blood O2 saturation profiles akin to those occurring during sleep apnea as well as in mice exhibiting natural sleep apnea. Conceptual innovation- Cellular and molecular mechanisms underlying the sympathetic activation by CIH proposed in this program are novel, which in addition to sleep apnea may also be applicable to other cardiorespiratory diseases. Major technical innovation includes assessing the significance of findings from experimental rodent model of IH in a naturally occurring sleep apnea mouse model. Investigators in this program have demonstrated expertise at the cellular, molecular, and systems levels of investigation and have strong record of collaborations. Completion of the program is anticipated to provide important insights for developing novel therapeutic strategies for alleviating autonomic co-morbidities associated with IH, which is a major manifestation of sleep apnea. Because of the tight thematic linkages across the projects, the total knowledge gained from the overall program will truly be greater than the sum derived from each project.