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:10330441
- 负责人:
- 金额:$ 68.05万
- 依托单位:
- 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:
- 关键词:AffectAngiotensin Type 1a ReceptorAngiotensinsAnimal ModelBiological MarkersBlood PressureBrainBrain-Derived Neurotrophic FactorCardiovascular DiseasesCellsChloridesChronicDataDiagnosisDiseaseElectrodesElectrophysiology (science)EquilibriumGene ExpressionGenetic TranscriptionGoalsHypertensionHypoxemiaHypoxiaImageIn VitroLamina TerminalisLesionMediatingModalityModelingNerveNeuronsNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IPathogenesisPatientsPeripheralPhysiologicalPopulationPotassium ChloridePressoreceptorsRadioRattusRenin-Angiotensin SystemResearchRhodopsinRoleSignal TransductionSleep Apnea SyndromesSliceSodium-Potassium-Chloride SymportersSubfornical OrganSynapsesSystemTelemetryTestingawakebasecarbon fibercardiovascular disorder riskcardiovascular risk factorexperimental studygamma-Aminobutyric Acidin vivoin vivo imagingnoveloptogeneticsparaventricular nucleuspatch clamppreoptic nucleuspressurepresynapticpreventprogramssynaptic functiontemporal 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.
该研究计划的中心目标是确定中枢神经系统在高血压相关疾病中的作用
慢性间歇性缺氧(CIH),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
表明正中视前核(MnPO)有助于CIH产生的持续性高血压,
大鼠这些实验将研究3种可能使MnPO有助于CIH的新机制
高血压我们的工作假设,基于我们以前的研究,是CIH触发FosB转录,
涉及血管紧张素II(ANG II)和NO信号传导的活性,以增加引起BDNF驱动的增加的兴奋
细胞内氯化物。这些效应将进一步增加兴奋并减少或逆转抑制
动脉压力感受器在一天的常氧时段期间促进持续的CIH HTN。
具体目的1:检测血管紧张素信号传导在CIH HTN中MnPO兴奋增加中的作用。
假设:血管紧张素信号增加增加PVN投射MnPO神经元的活性。
目的1将量化脑血管紧张素系统对PVN投射MnPO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,膜片钳电生理学,在体内
记录交感神经活性和MnPO单单位活性。
具体目标2:测试NO在增加CIH HTN中MnPO激发中的作用。
假设:MnPO中nos1的表达和活性增加增加了突触前兴奋,
持续CIH高血压。
目的2将检验由CIH触发的nos1表达和活性增加增加的假设。
PVN投射MnPO神经元的突触前兴奋。该机制将使用体外
电生理学和配对的实时测量NO与碳纤维电极和MRI-2成像,在
交感神经活动的体内记录,以及用无线电遥测技术的慢性血压记录。
具体目标3:确定减少/逆转GABA抑制和BDNF对脑缺血再灌注损伤的影响。
MnPO兴奋性、突触功效和CIH HTN。
假设:CIH触发BDNF神经元,其减少/逆转MnPO神经元中的GABA抑制。
目的3将确定BDNF是否减少/逆转PVN投射MnPO中GABA对压力感受器的抑制
神经元通过氯化物转运体如钠钾氯化物协同转运体1(NKCC 1)和/或
氯化钾协同转运蛋白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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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J Thomas Cunningham其他文献
J Thomas Cunningham的其他文献
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{{ truncateString('J Thomas Cunningham', 18)}}的其他基金
Intermittent hypoxia and hypertension: Role of the lamina terminalis
间歇性缺氧和高血压:终板的作用
- 批准号:
10548872 - 财政年份:2021
- 资助金额:
$ 68.05万 - 项目类别:
Neural Regulation of Vasopressin Release in a Model of Dilutional Hyponatremia
稀释性低钠血症模型中加压素释放的神经调节
- 批准号:
9895545 - 财政年份:2018
- 资助金额:
$ 68.05万 - 项目类别:
Homeostatic Regulation of Supraoptic Neurons: Role of BDNF
视上神经元的稳态调节:BDNF 的作用
- 批准号:
8835145 - 财政年份:2014
- 资助金额:
$ 68.05万 - 项目类别:
Homeostatic Regulation of Supraoptic Neurons: Role of BDNF
视上神经元的稳态调节:BDNF 的作用
- 批准号:
8695603 - 财政年份:2014
- 资助金额:
$ 68.05万 - 项目类别:
Homeostatic Regulation of Supraoptic Neurons: Role of BDNF
视上神经元的稳态调节:BDNF 的作用
- 批准号:
9242065 - 财政年份:2014
- 资助金额:
$ 68.05万 - 项目类别:
Intermittent Hypoxia-Induced Hypertension: Roles of Angiotensin and Chloride Transport in the Lamina Terminalis.
间歇性缺氧引起的高血压:血管紧张素和氯离子转运在终层中的作用。
- 批准号:
9253104 - 财政年份:2008
- 资助金额:
$ 68.05万 - 项目类别:
Intermittent Hypoxia-Induced Hypertension: Roles of Angiotensin and Chloride Transport in the Lamina Terminalis.
间歇性缺氧引起的高血压:血管紧张素和氯离子转运在终层中的作用。
- 批准号:
9096158 - 财政年份:2008
- 资助金额:
$ 68.05万 - 项目类别:
CONTROL OF SODIUM INTAKE IN THE HINDLIMB UNWEIGHTED RAT
后肢未体重大鼠钠摄入量的控制
- 批准号:
6628586 - 财政年份:2001
- 资助金额:
$ 68.05万 - 项目类别: