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）被认为是一个重要的决定因素