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

脑昂.

• 批准号: 8651936
• 负责人: Robin L Davisson
• 金额: $ 50.53万
• 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/8651936
• 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) 与肥胖引起的高血压 (HT) 有关，但其机制尚不清楚。我们的初步数据支持大脑 ANG 信号传导在饮食诱导肥胖 (DIO) 小鼠动脉压 (AP) 升高中的作用。其他数据揭示了 DIO 中关键脑心血管控制区（SFO-PVN 轴）显着的内质网 (ER) 应激，并表明 ER 应激的化学操作会影响该模型中的交感神经活动 (SNA) 和 AP。我们的数据还表明，DIO 会导致 SFO-PVN 轴氧化应激，这与 ER 应激有关。此外，新的初步数据表明，该脑轴中的内质网应激和氧化应激均与 DIO 小鼠的瘦素信号传导相关。其他新数据提出了 DIO 介导的大脑氧化和 ER 应激调节大脑 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且相互关联的概念：1）肥胖-HT中控制能量稳态和心血管反应的中央机制之间的分离； 2）脑内质网应激（一种新的疾病范式）作为关键的潜在机制； 3) 氧化还原信号传导在肥胖-HT 中的作用，与 ER 应激途径有潜在联系；4) SFO-PVN 轴在 DIO 介导的心血管和代谢失调中起着主要作用。我们将提出一个总体假设，即在 DIO 小鼠中，大脑 ANG 和/或瘦素信号传导的增加会促进 SFO-PVN 轴中的 ER 应激和氧化应激。我们推测，这种 ER/氧化应激导致 DIO 小鼠肾脏 SNA 和 AP 增加，但相反，在 SFO-PVN 轴上发挥作用，减弱或逆转脑 ANG 和/或瘦素介导的肥胖 HTN 模型中生热 SNA 和 EE 的促进作用。为了解决这一创新假设，我们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，允许大脑对关键 ANG、氧化剂和 ER 应激分子进行位点选择性靶向； 2) 最先进的内质网应激可视化和量化分析方法； 3) 用于评估 AP、SNA 和 EE 的复杂综合生理学。该项目的一个显着优势是与项目 2 和 3 的概念和技术方面的广泛接口。