Brain Ang. in Obesity-Induced Hypertension: Role of ER, Oxidant, & Leptin Stress

脑昂.

• 批准号: 8524229
• 负责人: Robin L Davisson
• 金额: $ 50.3万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8524229
• 关键词: Ablation; Address; Adipose tissue; Angiotensin II; Attenuated; Biological Assay; Biological Markers; Brain; Brain region; Cardiovascular system; Cell Nucleus; Chemicals; Complement; Coupled; Data; Defect; Diet; Disease; Dissociation; Employee Strikes; Endoplasmic Reticulum; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Functional disorder; GRP78 gene; Genes; Genetic; Genetically Engineered Mouse; Homeostasis; Hypertension; Hypothalamic structure; Instruction; Kidney; Leptin; Link; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Molecular Chaperones; Mus; Nerve; Obese Mice; Obesity; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peripheral; Phosphorylation; Physiological; Physiology; Prosencephalon; Proteins; Reactive Oxygen Species; Research; Resistance; Risk; Role; Signal Transduction; Site; Stress; Subfornical Organ; Sympathetic Nervous System; Testing; Viral; Viral Vector; base; blood pressure regulation; endoplasmic reticulum stress; global health; human CYBA protein; innovation; interdisciplinary approach; leptin receptor; model design; mouse model; mutant; neuroregulation; novel; oxidant stress; paraventricular nucleus; pressure; response; tool; viral gene delivery

The sympathetic nervous system and angiotensin II (ANG) are implicated in obesity-induced hypertension (HT), but the mechanisms are poorly defined. Our preliminary data support a role for brain ANG signaling in increased arterial pressure (AP) in diet-induced obese (DIO) mice. Additional data reveal striking endoplasmic reticulum (ER) stress in key brain cardiovascular control regions (SFO-PVN axis) in DIO and indicate that chemical manipulation of ER stress influences sympathetic nerve activity (SNA) and AP in this model. Our data also demonstrate that DIO causes oxidative stress in the SFO-PVN axis and this is linked to ER stress. Furthermore, new preliminary data show that both ER stress and oxidative stress in this brain axis are coupled to leptin signaling in DIO mice. Additional new data raise the possibility that DIO-mediated oxidative and ER stress in the brain modulate the facilitatory effect of brain ANG on energy expenditure (EE). Based on these promising, multifaceted preliminary data, we will address four innovative and interrelated concepts: 1) dissociation between central mechanisms controlling energy homeostasis and cardiovascular responses in obesity-HT; 2) brain ER stress, a new disease paradigm, as a key underlying mechanism; 3) the role of redox signaling, with potential links to ER stress pathways, in obesity-HT and 4) the SFO-PVN axis as a major player in DIO-mediated cardiovascular and metabolic dysregulation. We will address the overall hypothesis that in DIO mice, increased brain ANG and/or leptin signaling promotes ER stress and oxidant stress in the SFO-PVN axis. We postulate that this ER/oxidant stress contributes to the increased renal SNA and AP in DIO mice, but conversely acts in the SFO-PVN axis to blunt or reverse brain ANG- and/or leptin-mediated facilitatory effects on thermogenic SNA and EE in this model of obesity-HTN. To address this innovative hypothesis, we have assembled multiple sophisticated research tools, including 1) genetically engineered mouse models and viral vectors that allow brain site-selective targeting of key ANG, oxidant and ER stress molecules; 2) state-of-the-art assays for visualizing and quantifying ER stress; 3) sophisticated integrative physiology for evaluating AP, SNA and EE. A notable strength ofthe project is the extensive interfacing, both conceptual and technical, with Projects 2 and 3.

交感神经系统和血管紧张素II（ANG）参与肥胖引起的高血压（HT），但其机制尚不清楚。我们的初步数据支持脑ANG信号在饮食诱导肥胖（DIO）小鼠动脉压（AP）升高中的作用。额外的数据揭示了DIO中关键脑心血管控制区域（SFO-PVN轴）中显著的内质网（ER）应激，并表明ER应激的化学操作影响该模型中的交感神经活性（SNA）和AP。我们的数据还表明，DIO导致SFO-PVN轴中的氧化应激，这与ER应激有关。此外，新的初步数据表明，在DIO小鼠中，该脑轴中的ER应激和氧化应激都与瘦素信号传导相关联。额外的新数据提高了DIO介导的氧化和ER应激在大脑中调节脑ANG对能量消耗（EE）的促进作用的可能性。基于这些有希望的、多方面的初步数据，我们将讨论四个创新的和相互关联的概念：1）控制肥胖-HT能量稳态和心血管反应的中枢机制之间的分离; 2）脑ER应激，一种新的疾病范式，作为一个关键的潜在机制; 3）氧化还原信号传导的作用，与ER应激途径的潜在联系，在肥胖-HT和4）SFO-PVN轴作为一个主要的球员在DIO介导的心血管和代谢失调。我们将解决的总体假设，在DIO小鼠，增加脑血管紧张素和/或瘦素信号促进ER应激和氧化应激的SFO-PVN轴。 我们推测，这种ER/氧化应激有助于DIO小鼠肾脏SNA和AP的增加，但相反地，在SFO-PVN轴中起作用，以钝化或逆转脑ANG和/或瘦素介导的对肥胖-HTN模型中产热SNA和EE的易化作用。为了解决这一创新假设，我们已经组装了多种复杂的研究工具，包括1）基因工程小鼠模型和病毒载体，允许大脑位点选择性靶向关键ANG，氧化剂和ER应激分子; 2）用于可视化和定量ER应激的最先进测定; 3）用于评估AP、SNA和EE的复杂综合生理学。该项目的一个显著优势是与项目2和3在概念和技术上的广泛接口。