Integrative Consequences of Intermittent Hypoxia

项目摘要--总体 本申请是为一项名为“间歇性缺氧的综合后果”的新项目拨款而提出的。 慢性间歇性低氧(Cih)是睡眠呼吸暂停的典型表现，睡眠呼吸暂停是一种常见的呼吸道疾病。 仅在美国就影响了数百万人的疾病。患有睡眠呼吸暂停和啮齿动物暴露于 该病表现为交感神经系统过度活跃，与许多病理改变有关。 由睡眠呼吸暂停引起的。拟议计划的总体目标是确定CIH如何导致 交感神经激活并确定其后果。该计划的具体目标是：目标1-- 确定了IH激活交感神经的神经机制(S)。外围和中央 与CIH激活交感神经有关的神经机制将在项目1和 2.目标2--CIH激活交感神经的后果，该问题将在项目3中通过确定 交感神经激活在血管内皮细胞激活中的作用目标3-阐明表观遗传学 CIH诱导交感神经激活的潜在机制，这将是项目4的重点。 项目将得到一个行政核心和一个科学核心的支持。该计划中的研究利用 暴露在IH模式下的啮齿动物，模拟了类似于在 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激活交感神经的机制是新颖的，它在 除了睡眠呼吸暂停，其他心肺疾病也可能适用。重大技术创新 包括评估实验性IH啮齿动物模型在自然发生的 睡眠呼吸暂停小鼠模型。这个项目的研究人员已经展示了在手机上的专业知识， 具有分子和系统层面的研究经验，并有很强的合作记录。已完成的 该计划有望为开发新的治疗策略提供重要的见解 与IH相关的自主神经并存，这是睡眠呼吸暂停的主要表现。因为 项目之间紧密的主题联系，从整个计划中获得的总知识将真正 大于每个项目得出的总和。

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.