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

脑昂.

基本信息

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
项目类别：
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

项目摘要

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，但机制的定义很差。我们的初步数据支持在饮食诱导的肥胖（DIO）小鼠中增加动脉压（AP）中脑ANG信号的作用。其他数据揭示了关键的心血管控制区域（SFO-PVN轴）中引人注目的内质网应激（ER）应激，并表明对ER应力的化学操纵会影响该模型的交感神经活动（SNA）和AP。我们的数据还表明，DIO在SFO-PVN轴上引起氧化应激，这与ER应力有关。此外，新的初步数据表明，该脑轴中的ER应力和氧化应激均与DIO小鼠中的瘦素信号耦合。其他新数据提出了DIO介导的大脑中氧化和ER应力调节脑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初步数据，我们将解决四个创新和相互关联的概念：1）控制能量稳态的中心机制与肥胖症中的心血管反应之间的解离； 2）脑ER应激，一种新的疾病范式，作为一种基本机制； 3）在肥胖-HT和4）氧化还原信号传导的作用，具有与ER应力途径的潜在联系。我们将解决这样的总体假设，即在DIO小鼠中，增加了脑ANG和/或瘦素信号传导会促进SFO-PVN轴中的ER应激和氧化剂应激。我们假设这种ER/氧化剂应力有助于DIO小鼠中肾脏SNA和AP的增加，但相反，在SFO-PVN轴上起作用，可在这种肥胖-HTN模型中钝化或反向脑ang或逆转脑ANG和/或瘦素介导的对热SNA和EE的促进作用。为了解决这一创新的假设，我们组装了多个复杂的研究工具，包括1）基因工程的小鼠模型和病毒载体，这些模型允许大脑位点选择性靶向关键ANG，氧化剂和ER应力分子； 2）可视化和量化ER应力的最先进测定； 3）用于评估AP，SNA和EE的复杂整合生理。该项目的一个显着优势是项目2和3的广泛接口，无论是概念还是技术的。