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

 描述(由申请人提供)：睡眠呼吸暂停对健康构成重大风险，并与血压升高和夸大的交感神经放电有关。 动物夜间慢性暴露于间歇性低氧(CIH)可模拟睡眠呼吸暂停期间反复发作的动脉低氧血症。暴露于CIH的大鼠会出现持续性的血压升高和交感神经流出，就像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，我们的项目为CIH如何改变中枢神经系统交感调节神经元之间的突触处理以及这些变化如何导致交感神经放电持续增加和血压持续上升提供了新的见解。该计划的目标是解决中枢神经系统内调节CIH引起的高血压和交感神经系统活动增加的机制，并为潜在的治疗目标和策略提供见解。我们的工作表明，在接触CIH的前7天内，血压的持续升高依赖于动脉化学感受器、HPA轴和作用于前脑的血管紧张素(Ang II)。由S.Mifflin领导的项目1将检验这样一个假设，即CH重复激活动脉化学感受器会导致孤束核(NTS)神经元活动依赖性的变化，而NTS调节交感神经和HPA轴功能。由T.Cunningham领导的项目2将检验这一假设，即在CIH期间肾素-血管紧张素系统的活性增加导致终板神经元投射到PVN并增加交感神经流出的活动依赖性变化。由G.Toney领导的项目3将测试这一假设，即化学感受器和AngⅡ敏感的输入诱导交感兴奋的PVN神经元的活动依赖的变化，从而增加它们的放电和兴奋性，并且这些适应在面临缺血时实际上可能是保护的。实现这些项目的目标将由2个核心设施(行政、 分析)。分析核心将提供对基因表达和蛋白质水平的基因组和蛋白质组分析，以及蛋白质的翻译后修饰。这些研究将确定调节神经元可塑性的机制，并在脑出血高血压的发展中起重要作用。这一结果还将有助于我们理解与中枢神经系统缺氧(心力衰竭、中风)以及其他钠依赖和血管依赖高血压模型(肥胖)相关的其他情况。

 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).