Role of the brain Renin-Angiotensin Sys. in Cardiovas and Metabolic Regulation

脑中的肾素-血管紧张素系统（RAS）被公认为是脑缺血的重要决定因素。 心血管调节，通过其对动脉压，液体稳态和交感神经的作用 活动，并与高血压有关。越来越多的证据表明， RAS，在大脑和外周也调节能量消耗。然而，准确的中央和 血管紧张素II（ANG）调节能量稳态的外周机制，其 大脑中的生产和行动，涉及的神经回路，以及它与其他途径的整合 控制进食和能量平衡仍然不明确。同样，目前尚不清楚， 调节ANG心血管与代谢作用的机制和传出途径是 相似或不同。在上一个资助期间，我们报告了推进这一概念的令人信服的数据 大脑中血管紧张素能信号的激活导致能量消耗增加。我们 总的假设是，有不同的中枢机制控制心血管和 脑RAS激活后的代谢输出，以及脑中ANG的局部合成控制 动脉压、水摄入量和能量消耗，通过重叠但离散的ANG依赖性 机制和传出通路。我们进一步假设脂肪RAS通过AT2R 调节大脑RAS对脂肪组织的作用，而饮食诱导的肥胖（DIO）会削弱大脑RAS的功能。 脑RAS激活对能量消耗的影响，通过刺激脂肪RAS作用， AT2R依赖机制。该提案的目的是解决以下假设。1)ang SFO和PVN中的血管紧张素生成和血管紧张素能信号传导是动脉粥样硬化的关键介质。 压力、水摄入和能量消耗对外源性和内源性脑RAS的反应 2）脑RAS活性增加的作用受脂肪RAS活性的调节 由DIO诱导并由AT2R依赖性机制介导; 3）内质网（ER）应激， SFO和PVN在动脉压、水摄入和能量消耗中起重要作用 增加大脑RAS活性的反应。我们将利用令人兴奋的新的初步数据， 利用概念上的进步和研究人员在遗传学方面的独特专业知识， 神经控制机制、神经解剖学以及复杂的心血管和代谢表型。 一个独特的优势是与其他项目的广泛的智力和技术互动。 相关性（见说明）： 这些研究对于提出以下概念具有重要意义：a）不同的中枢机制， 脑RAS调节动脉压、水摄入和能量消耗，B）新的整合 在中枢和脂肪RAS之间，和c）ER应激作为脑中的新型信号传导方式。的 这些研究在采用最先进的基因模型和技术进行基因切除方面具有创新性， 大脑，先进的心血管，代谢和ER应激监测

The renin-angiotensin system (RAS) in the brain is well recognized as an important determinant of cardiovascular regulation, through its actions on arterial pressure, fluid homeostasis and sympathetic nerve activity, and has been implicated in hypertension. Growing evidence has advanced the concept that the RAS, both in the brain and periphery also regulates energy expenditure. However, the precise central and peripheral mechanisms by which angiotensin II (ANG) regulates energy homeostasis, its sites of production and action in the brain, the neural circuitry involved, and its integration with other pathways controlling feeding and energy homeostasis remain undefined. Similarly, it remains unclear if the mechanisms and efferent pathways regulating the cardiovascular versus metabolic actions of ANG are similar or distinct. During the previous funding period we reported compelling data advancing the concept that activation of angiotensinergic signaling in the brain results in increased energy expenditure. Our overall hypothesis is that there are differential central mechanisms controlling the cardiovascular and metabolic outputs following brain RAS activation, and that local synthesis of ANG in the brain controls arterial pressure, water intake, and energy expenditure through overiapping yet discrete ANG-dependent mechanisms and efferent pathways. We further hypothesize that the adipose RAS through AT2R modulates the actions of the brain RAS on adipose tissue, and that diet-induced obesity (DIO) blunts the effects of brain RAS activation on energy expenditure by stimulating the adipose RAS acting through an AT2R-dependent mechanism. The aims ofthe proposal are to address the following hypotheses. 1) ANG production and angiotensinergic signaling in the SFO and PVN are critical mediators of the arterial pressure, water intake, and energy expenditure responses to exogenous and endogenous brain RAS activation; 2) The effects of increased brain RAS activity are modulated by the activity ofthe adipose RAS induced by DIO and mediated by an AT2R-dependent mechanism; 3) Endoplasmic reticulum (ER) stress in the SFO and PVN plays an important role in the arterial pressure, water intake, and energy expenditure responses to increased brain RAS activity. We will capitalize on exciting new preliminary data, and leverage conceptual advances and the unique expertise of the investigators in this program in genetics, neural control mechanisms, neuroanatomy, and sophisticated cardiovascular and metabolic phenotyping. A distinctive strength is the extensive intellectual and technical interactions with the other projects. RELEVANCE (See Instructions): These studies are significant in advancing the concepts of a) differential central mechanisms by which the brain RAS regulates arterial pressure, water intake, and energy expenditure, b) novel integration between the central and adipose RAS, and c) ER stress as a novel signaling modality in the brain. The studies are innovative in employing state-of-the-art genetic models and techniques for gene ablation in the brain, and advanced cardiovascular, metabolic and ER stress monitoring