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

交感神经系统和血管紧张素II （ANG）与肥胖性高血压（HT）有关，但其机制尚不明确。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。其他数据显示，在DIO中，关键的脑心血管控制区域（SFO-PVN轴）的内质网（ER）应激显著，并表明内质网应激的化学操纵影响了该模型中交感神经活动（SNA）和AP。我们的数据还表明，DIO引起SFO-PVN轴的氧化应激，这与内质网应激有关。此外，新的初步数据显示，在DIO小鼠中，内质网应激和氧化应激都与瘦素信号耦合。额外的新数据提出了大脑中dio介导的氧化应激和内质网应激调节脑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，我们将解决四个创新的和相互关联的概念：1)肥胖- ht中控制能量稳态和心血管反应的中枢机制之间的分离；2)脑内质网应激是一种新的疾病范式，是其重要的潜在机制；3)氧化氧化信号在肥胖- ht中的作用，与内质网应激途径的潜在联系；4)SFO-PVN轴在dio介导的心血管和代谢失调中起主要作用。我们将解决DIO小鼠的总体假设，即增加的脑ANG和/或瘦素信号可促进SFO-PVN轴的内质网应激和氧化应激。我们假设这种内质网/氧化应激有助于DIO小鼠肾脏SNA和AP的增加，但反过来在SFO-PVN轴上起作用，减弱或逆转这种肥胖- htn模型中ANG和/或瘦素介导的对热源SNA和EE的促进作用。为了解决这一创新的假设，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，允许关键的ANG，氧化剂和内质网应激分子的大脑位点选择性靶向；2)最先进的内质网应力可视化和量化分析；3)复杂的综合生理学评估AP、SNA和EE。项目的一个显著优势是与项目2和项目3在概念和技术上进行了广泛的对接。

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.