Intermittent hypoxia and hypertension: Role of the lamina terminalis

间歇性缺氧和高血压：终板的作用

基本信息

批准号：
10548872
负责人：
J Thomas Cunningham
金额：
$ 68.05万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-18 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548872
关键词：
Affect Angiotensin II Angiotensin Type 1a Receptor Angiotensins Animal Model Biological Markers Blood Pressure Brain Brain-Derived Neurotrophic Factor Cardiovascular Diseases Cells Chlorides Chronic Data Diagnosis Disease Electrodes Electrophysiology (science)Gene Expression Genetic Transcription Goals Hypertension Hypoxemia Hypoxia Image In Vitro Lamina Terminalis Lesion Maps Mediating Modality Modeling Nerve Neurons Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Pathogenesis Patients Peripheral Physiological Population Pressoreceptors Radio Rattus Renin-Angiotensin System Research Rhodopsin Role Signal Transduction Sleep Apnea Syndromes Slice Sodium-Potassium-Chloride Symporters Subfornical Organ Synapses System Telemetry Testing awake carbon fiber cardiovascular disorder risk cardiovascular risk factor chloride-cotransporter potassium experimental study gamma-Aminobutyric Acid in vivo novel optogenetics paraventricular nucleus patch clamp preoptic nucleus pressure presynaptic prevent programs synaptic function temporal measurement

项目摘要

The central objective of this research program is to determine the role of the CNS in hypertension associated with chronic intermittent hypoxia (CIH), a model of hypoxemia associated with sleep apnea. Our previous results indicate that the median preoptic nucleus (MnPO) contributes to the sustained hypertension produced by CIH in rat. These experiments will investigate 3 novel mechanisms that may allow the MnPO to contribute to CIH hypertension. Our working hypothesis, based on our previous studies, is that CIH triggers FosB transcriptional activity involving angiotensin II (ANG II) and NO signaling to increase excitation causing BDNF-driven increases in intracellular chloride. These effects would further increase excitation and reduce or reverse inhibition from arterial baroreceptors promoting sustained CIH HTN during normoxic periods of the day. Specific Aim 1: Test the role of angiotensin signaling in increased MnPO excitation in CIH HTN. Hypothesis: Increased angiotensin signaling increases the activity of PVN-projecting MnPO neurons. Aim 1 will quantify the contribution of the brain angiotensin system to increased activity in PVN-projecting MnPO neurons using angiotensin “sniffer cells” 19 combined with optogenetics, patch clamp electrophysiology, in vivo recording of sympathetic nerve activity, and MnPO single unit activity. Specific Aim 2: Test the role of NO in increasing MnPO excitation in CIH HTN. Hypothesis: Increased expression and activity of nos1 in MnPO increases presynaptic excitation to drive sustained CIH hypertension. Aim 2 will test the hypothesis that the increase of nos1 expression and activity triggered by CIH increases presynaptic excitation in PVN projecting MnPO neurons. This mechanism will be tested using in vitro electrophysiology and paired real-time measurements of NO with carbon fiber electrodes and DAF-2 imaging, in vivo recording of sympathetic nerve activity, and chronic blood pressure recording with radio telemetry. Specific Aim 3: Determine the contribution of reduced/reversed GABA inhibition and BDNF to changes in MnPO excitability, synaptic efficacy, and CIH HTN. Hypothesis: CIH triggers BDNF neurons that reduces/reverses GABA inhibition in MnPO neurons. Aim 3 will determine if BDNF reduces/reverses baroreceptor inhibition by GABA in PVN-projecting MnPO neurons though chloride transports such as sodium potassium chloride cotransporter 1 (NKCC1) and/or potassium chloride cotransporter2 (KCC2). These experiments will use live cell chloride imaging, brain slice and in vivo electrophysiology, and channel rhodopsin assisted circuit mapping.

该研究计划的核心目的是确定中枢神经系统在相关的高血压中的作用与慢性间歇性缺氧（CIH）一起，一种与睡眠呼吸暂停相关的低氧血症模型。我们以前的结果表明中位前核（MNPO）有助于CIH产生的持续性高血压鼠。这些实验将研究3种新的机制，这些机制可能使MNPO有助于CIH 高血压。基于我们以前的研究，我们的工作假设是CIH触发FOSB转录涉及血管紧张素II（ANG II）的活性和没有信号传导以增加兴奋，从而导致BDNF驱动的增加在细胞内氯化物中。这些影响将进一步增加兴奋，并减少或逆转抑制在一天中的常氧时期促进持续的CIH HTN的动脉压力感受器。具体目标1：测试血管紧张素信号传导在CIH HTN中MNPO兴奋增加中的作用。假设：血管紧张素信号的增加增加了PVN投射MNPO神经元的活性。 AIM 1将量化脑血管紧张素系统对PVN投影MNPO的活性增加的贡献神经元使用血管紧张素“嗅探细胞” 19结合光遗传学，斑块电生理学，体内记录交感神经活动和MNPO单位活性。具体目标2：测试NO在增加CIH HTN中MNPO兴奋中的作用。假设：NOS1在MNPO中的表达和活性增加会增加突触前兴奋以驱动持续的CIH高血压。 AIM 2将检验以下假设：NOS1表达的增加和CIH触发的活性 PVN投射MNPO神经元的突触前兴奋。该机制将使用体外测试电生理学和与碳纤维电极和DAF-2成像的NO配对实时测量通过射电遥测记录交感神经活动和慢性血压记录的体内记录。特定目标3：确定减少/反向GABA抑制和BDNF对变化的贡献 MNPO兴奋性，突触效率和CIH HTN。假设：CIH会触发BDNF神经元，可减少/逆转MNPO神经元中的GABA抑制作用。 AIM 3将确定BDNF是否会减少/逆转pvn-projection mnpo中GABA抑制压力感受器神经元虽然氯化物运输，例如氯化钠氯化钾共转运蛋白1（NKCC1）和/或氯化钾共转运蛋白2（KCC2）。这些实验将使用活细胞氯化物成像，脑切片和体内电生理学和通道视紫红质辅助电路映射。