Neurohumoral Adaptations to Chronic Intermittent Hypoxia: Insights into the Pathophysiology of Sleep Apnea

 描述（由申请人提供）：睡眠呼吸暂停会对健康造成重大风险，并与血压升高和交感神经放电过度有关。 动物在夜间长期暴露于间歇性缺氧（CIH）中，模拟了睡眠呼吸暂停期间发生的动脉低氧血症的反复发作。暴露于CIH的大鼠出现持续升高的血压和交感神经流出，如在患有睡眠呼吸暂停的人类中观察到的那样。在过去的资助期间，我们的项目提供了新的见解，CIH如何改变中枢神经系统交感神经调节神经元之间的突触处理，以及这些改变如何导致交感神经放电持续上升和血压持续升高。 该计划的目标是解决中枢神经系统内介导CIH诱导的高血压和交感神经系统活动升高的机制，并提供对潜在治疗靶点和策略的见解。我们的工作已经证明，在暴露于CIH的前7天血压的持续升高依赖于动脉化学感受器，HPA轴和血管紧张素（ANG II）在前脑内的作用。提出了三个项目：项目1，由S。Mifflin，将测试的假设，反复激活动脉化学感受器的CH诱导活动依赖性的变化，在孤束核（NTS），调节交感神经和HPA轴功能的神经元。项目2，由T. Cunningham，将测试这一假设，即在CIH期间增加的肾素-血管紧张素系统的活性诱导终板中投射到PVN的神经元的活性依赖性变化，并增加交感神经流出。项目3，由G. Toney将检验以下假设：化学感受器和ANG II敏感性输入诱导交感神经兴奋性PVN神经元的活性依赖性变化，其增加其放电和兴奋性，并且这些适应在面临缺血时实际上可能是保护性的。 实现这些项目的目标将由两个核心设施（行政、 分析的）。分析核心将提供基因表达和蛋白质水平的基因组和蛋白质组学分析以及蛋白质的翻译后修饰。这些研究将确定介导神经元可塑性的机制，并在CIH高血压的发展中发挥重要作用。该结果还将与我们对与中枢神经系统缺氧（心力衰竭、中风）相关的其它病症以及其它钠依赖性和ANG II依赖性高血压模型（肥胖）的理解相关。

 DESCRIPTION (provided by applicant): Sleep apnea poses a significant health risk and is associated with increased blood pressure and exaggerated sympathetic nerve discharged. Chronic exposure to intermittent hypoxia (CIH) during the nocturnal period in animals mimics the repetitive bouts of arterial hypoxemia that occur during sleep apnea. Rats exposed to CIH develop a persistently elevated blood pressure and sympathetic outflow as observed in humans with sleep apnea. During the past funding period our program provided novel insights into how CIH alters synaptic processing among sympathetic regulatory neurons in the central nervous system and how these alterations lead to a persistent rise in sympathetic nerve discharge and a sustained increase in blood pressure. The Program objectives are to address mechanisms within the central nervous system that mediate CIH-induced hypertension and elevated sympathetic nervous system activity and to provide insights into potential therapeutic targets and strategies. Our work has demonstrated that the persistent increase in blood pressure during the first 7 days of exposure to CIH is dependent upon arterial chemoreceptor, the HPA axis and angiotensin (ANG II) acting within the forebrain. Three projects are proposed: Project 1, led by S. Mifflin, will test the hypothesis that repetitive activation of the arterial chemoreceptors by CH induces activity-dependent changes in neurons in the nucleus of the solitary tract (NTS) that regulate sympathetic and HPA axis function. Project 2, led by T. Cunningham, will test the hypothesis that increased activity of the renin-angiotensin system during CIH induces activity-dependent changes in neurons in the lamina terminalis that project to the PVN and increase sympathetic outflow. Project 3, led by G. Toney, will test the hypothesis that chemoreceptor- and ANG ll-sensitive inputs induce activity dependent changes in sympatho-excitatory PVN neurons that increase their discharge and excitability and that these adaptations may actually be protective when faced with ischemia. Achieving the goals of these projects will be facilitated by 2 Core facilities (Administrative, Analytical). The Analytical Core will provide genomic and proteomic analysis of gene expression and protein levels as well as post-translational modifications of proteins. The studies will determine mechanisms that mediate neuronal plasticity and are important in the development of CIH-hypertension. The results will also have relevance to our understanding of other conditions associated with central nervous system hypoxia (heart failure, stroke) and other sodium dependent and ANG ll-dependent models of hypertension (obesity).