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

大脑肾素-血管紧张素系统的作用。

• 批准号: 8651937
• 负责人: Curt Daniel Sigmund
• 金额: $ 51.81万
• 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/8651937
• 关键词: AGTR2 gene; Ablation; Address; Adipose tissue; Agonist; Angiotensin II; Angiotensinogen; Angiotensins; Biological Markers; Body Weight; Brain; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Complement; DOCA; Data; Diet; Efferent Pathways; Energy Metabolism; Funding; Genes; Genetic; Genetic Models; Genetic Techniques; Growth; Homeostasis; Hypertension; Instruction; Liquid substance; Mediating; Mediator of activation protein; Metabolic; Modality; Monitor; Mus; Nerve; Neuroanatomy; Obesity; Output; Pathway interactions; Peripheral; Phenotype; Play; Production; Protein Isoforms; Protocols documentation; Receptor Activation; Receptor Signaling; Regulation; Renin; Renin-Angiotensin System; Reporting; Research Personnel; Role; Signal Transduction; Site; Testing; Thermogenesis; Transgenic Organisms; Water consumption; blood pressure regulation; design; endoplasmic reticulum stress; energy balance; feeding; innovation; mind control; neural circuit; neuroregulation; novel; pressure; prevent; programs; receptor; response

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.

大脑中的肾素 - 血管紧张素系统（RAS）被广泛认为是重要的决定因素 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。越来越多的证据提出了这样一个概念 大脑和外围的RAS还调节能量消耗。但是，确切的中央和 血管紧张素II（ANG）调节能量稳态的外围机制，其部位 大脑中的生产和作用，涉及的神经电路及其与其他途径的整合 控制喂养和能量稳态仍然不确定。同样，还不清楚是否 调节ANG的心血管与代谢作用的机制和传出途径是 相似或独特。在上一个资金期间，我们报告了引人注目的数据推进了概念 大脑中血管紧力信号传导的激活导致能量消耗增加。我们的 总体假设是，控制心血管和 大脑RAS激活后的代谢输出以及脑控制中ANG的局部合成 通过过度依赖ANG依赖性的动脉压，摄入量和能量消耗 机制和传出途径。我们进一步假设脂肪通过AT2R 调节脑拉斯对脂肪组织的作用，饮食诱导的肥胖症（DIO）钝化 通过刺激作用的脂肪Ras，大脑RAS激活对能量消耗的影响 AT2R依赖机制。该提案的目的是解决以下假设。 1）Ang SFO和PVN中的生产和血管紧张信号传导是动脉的关键介体 压力，水的摄入量和能量消耗对外源和内源性脑RAS的反应 激活; 2）增加脑RAS活性的影响受脂肪Ras的活性调节 由DIO诱导并由AT2R依赖性机制介导； 3）内质网（ER）应力 SFO和PVN在动脉压，摄入量和能量消耗中起着重要作用 对增加大脑RAS活性的反应。我们将利用令人兴奋的新初步数据，并 利用概念的进步和研究人员在该计划中的独特专业知识，在遗传学方面， 神经控制机制，神经解剖学以及精致的心血管和代谢表型。 与其他项目的广泛智力和技术互动是一种独特的优势。