Novel Mechanism Regulating RAS Activity in the Brain: Role in Neurogenic Hypertension
调节大脑 RAS 活性的新机制:在神经源性高血压中的作用
基本信息
- 批准号:10213809
- 负责人:
- 金额:$ 47.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-06-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAllelesAngiotensin IIAngiotensinogenBloodBlood PressureBrainBudgetsCRISPR/Cas technologyCardiovascular systemCell LineCell NucleusCellsDOCADataDisinhibitionEnergy MetabolismExhibitsExonsExperimental Water DeprivationExposure toFutureGenerationsGenesGeneticGenetic TranscriptionHigh Fat DietHomeostasisHypertensionHypothalamic structureImpairmentIn VitroInactive ReninIntakeKidneyLightLiquid substanceMediatingMessenger RNAMetabolicMethodsModelingMolecularMusNerveNeurogliaNeuronsPathologicPeptide Signal SequencesPhysiologicalPlayPreventionProductionProsencephalonProtein IsoformsRegulationReninRenin-Angiotensin SystemReporterRoleSeminalSignal TransductionSiteSodium ChlorideStimulusStructure of nucleus infundibularis hypothalamiSubfornical OrganSympathetic Nervous SystemSystemTestingUpstream Enhancerdietaryextracellulargenetic manipulationgenome editinginhibitor/antagonistinnovationmouse modelneuroblastoma cellneurogenic hypertensionnovelparaventricular nucleuspreservationpromoterreceptorresponsestressorsynergism
项目摘要
Summary/Abstract
The brain renin-angiotensin system (RAS) plays a crucial role in regulating cardiovascular and metabolic
function. Nuclei-specific synthesis and action of angiotensin-II (ANG) in the brain affords mechanisms for the
independent regulation of fluid intake and sympathetic nerve activity (SNA) controlling blood pressure (BP) and
metabolic responses. That angiotensinogen (AGT), the substrate for renin and precursor to ANG is
constitutively released from glial cells throughout the brain, and from neurons in nuclei controlling
cardiovascular and metabolic function, implores the central question of how ANG production in the brain is
regulated? We identified an unexpected and novel mechanism regulating expression of renin in the brain
which may address this. However, the initiating signals and mechanisms involved remains unknown. This
project will examine the innovative concepts and hypotheses that: 1) there is coordinate regulation of renin
mRNA isoforms which controls RAS activity in the brain, and 2) impairment of this novel control mechanism
causes neurogenic hypertension and increases sensitivity of exposure to hypertension-causing stimuli. We will
examine this original concept in the following two specific aims: 1) test the hypothesis that coordinated
expression of Ren-b and Ren-a in the subfornical organ (SFO), paraventricular nucleus (PVN), and arcuate
nucleus (ARC) mediates local ANG production and action which alters SNA controlling cardiovascular and
metabolic function, and 2) test the hypothesis that disinhibition of Ren-a expression with concomitant inhibition
of renin-b expression in the SFO, PVN and ARC is required to mediate sensitization of the hypertensive
response (HTR) to mild humoral (e.g. ANG) and dietary (e.g. high fat diet) stressors. The studies will advance
the concepts that a) Ren-b expression is an endogenous inhibitor of Ren-a expression limiting ANG production
in the presence of excess extracellular AGT, and b) under conditions which threaten homeostasis (e.g. water
deprivation) or in response to pathological stimuli (e.g. DOCA-salt or high fat diet), previously dormant Ren-a
expression is disinhibited leading to site-specific prorenin activation, ANG generation and ANG action.
Importantly, we hypothesize that impairment of this regulatory circuit causes neurogenic hypertension. The
project has natural synergy as other projects that will similarly examine blood pressure and metabolic signaling
in forebrain and hypothalamic nuclei. Moreover, this project will be informed by the data collected by the other
projects and will synergize by exploring RAS-dependent and renin-dependent mechanisms in those systems.
摘要/文摘
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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Curt Daniel Sigmund其他文献
Curt Daniel Sigmund的其他文献
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{{ truncateString('Curt Daniel Sigmund', 18)}}的其他基金
PPARG-dependent Mechanisms Control Endothelial-Smooth Muscle Coordination, Arterial Pressure, Vasomotor Function and Arterial Stiffness
PPARG 依赖性机制控制内皮-平滑肌协调、动脉压、血管舒缩功能和动脉僵硬度
- 批准号:
10337230 - 财政年份:2019
- 资助金额:
$ 47.7万 - 项目类别:
PPARG-dependent Mechanisms Control Endothelial-Smooth Muscle Coordination, Arterial Pressure, Vasomotor Function and Arterial Stiffness
PPARG 依赖性机制控制内皮-平滑肌协调、动脉压、血管舒缩功能和动脉僵硬度
- 批准号:
10092211 - 财政年份:2019
- 资助金额:
$ 47.7万 - 项目类别:
PPARG-dependent Mechanisms Control Endothelial-Smooth Muscle Coordination, Arterial Pressure, Vasomotor Function and Arterial Stiffness
PPARG 依赖性机制控制内皮-平滑肌协调、动脉压、血管舒缩功能和动脉僵硬度
- 批准号:
10565914 - 财政年份:2019
- 资助金额:
$ 47.7万 - 项目类别:
PPG-Genetic and Signaling Mechanisms in the Central Regulation of Blood Pressure
PPG-血压中枢调节的遗传和信号机制
- 批准号:
9278663 - 财政年份:2016
- 资助金额:
$ 47.7万 - 项目类别:
Role of PPARG the PPARG Target Gene RBP7 in the Endothelium
PPARG 的作用 PPARG 靶基因 RBP7 在内皮细胞中的作用
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9249635 - 财政年份:2016
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$ 47.7万 - 项目类别:
Hypertension: Role of Smooth Muscle Cullin-3 and the CRL3 Complex
高血压:平滑肌 Cullin-3 和 CRL3 复合体的作用
- 批准号:
8956718 - 财政年份:2015
- 资助金额:
$ 47.7万 - 项目类别:
PPG-Genetic and Signaling Mechanisms in the Central Regulation of Blood Pressure
PPG-血压中枢调节的遗传和信号机制
- 批准号:
7433915 - 财政年份:2007
- 资助金额:
$ 47.7万 - 项目类别:
Novel Mechanism Regulating RAS Activity in the Brain: Role in Neurogenic Hypertension
调节大脑 RAS 活性的新机制:在神经源性高血压中的作用
- 批准号:
10445017 - 财政年份:2007
- 资助金额:
$ 47.7万 - 项目类别:
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