Central Renin-Angiotensin System: Metabolism, Fluid Balance, and Hypertension

中央肾素-血管紧张素系统：代谢、体液平衡和高血压

基本信息

批准号：
8458298
负责人：
Justin L Grobe
金额：
$ 24.9万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458298
关键词：
Ablation Adipocytes Adipose tissue Adult American Angiotensin II Angiotensinogen Angiotensins Animal Model Animals Anorexia Basal metabolic rate Blood Circulation Blood Pressure Blood Vessels Brain Brown Fat Cardiac Cardiovascular Diseases Cardiovascular Physiology Centers for Disease Control and Prevention (U.S.)Cessation of life Chronic Clinical Complex Consummatory Behavior Desire for food Development Diabetes Mellitus Digestive System Disorders Disease Doctor of Philosophy Eating Economics Exhibits Fluid Balance Foundations Functional disorder Genetic Goals Hormones Human Hyperactive behavior Hypertension Individual Institutes Instruction Investigation Kidney Kidney Diseases Knock-out Laboratories Lead Liquid substance Literature Maintenance Maps Mediating Mentors Metabolic Metabolic Control Metabolic Diseases Metabolism Modality Modeling Mus Myocardial Ischemia Neuraxis Neurons Neurotransmitters Obesity Overweight Patients Peptide Receptor Peptides Peptidyl-Dipeptidase A Peripheral Phase Phenotype Polydipsia Polyuria Population Productivity Receptor Signaling Regulation Renin Renin-Angiotensin System Research Resistance Risk Role Second Messenger Systems Series Signal Pathway Signal Transduction Sodium Solid Structure Supplementation Sympathetic Nervous System System Thermogenesis Tissues Transgenes Transgenic Animals Type 2 Angiotensin II Receptor Underweight United States Vasopressins Weight Gain Work cardiovascular risk factor cost disorder prevention energy balance innovation mortality new therapeutic target novel paracrine psychologic receptor recombinase research study second messenger social

项目摘要

Cardiovascular and metabolic disorders are rapidly growing burdens on tiuman hiealth worldwide. Currently approximately one third ofthe adult population ofthe United States is clinically obese, and one third exhibit sustained hypertension. There is also a high overlap of patients who exhibit both obesity and hypertension. Collectively, the economic, social, psychological, and productivity burdens which result from cardiovascular and metabolic disorders costs the United States roughly quarter of a trillion dollars per year. One hormone system involved in the regulation of both metabolism and cardiovascular function is the Renin-Angiotensin System (RAS). This system exists in the circulation as a classic hormone system, and also within individual orgains ofthe body where it acts in a paracrine fashion. While the RAS is found in many tissues throughout the body, we have demonstrated that hyperactivity of the brain RAS is sufficient to cause gross disturbances in blood pressure, fluid balance, and metabolic regulation. We have identified specific, distinct signaling mechanisms that mediate each of these phenotypes. The current proposal will narrowly focus on the mechanism of metabolic regulation by the brain RAS. Guided by our preliminary findings, we hypothesize that the brain RAS stimulates thermogenesis through two mechanisms. First, via activation of the sympathetic nervous system, the brain RAS stimulates thermogenesis within brown adipose tissue. Second, via a vasopressin-mediated hypertension, the brain RAS suppresses the circulating RAS. Suppression ofthe circulating RAS results in reduced angiotensin AT2 receptor signaling within white adipocytes and preadipocytes, which results in increased formation of brown adipocytes and thus increased thermogenic capacity. Together, these mechanisms synergistically act to positively influence metabolic rate. Examination of these mechanisms will likely lead to the identification of novel therapeutic targets for metabolic diseases.

心血管和代谢紊乱正在给全世界的 tiuman 健康带来迅速增长的负担。目前，美国大约三分之一的成年人口患有临床肥胖症，而另一第三表现出持续性高血压。同时表现出肥胖和肥胖的患者也有很高的重叠率。高血压。总的来说，经济、社会、心理和生产力负担心血管和代谢疾病每年给美国造成大约 25 万亿美元的损失。一种参与调节新陈代谢和心血管功能的激素系统是肾素-血管紧张素系统（RAS）。该系统作为经典的激素系统存在于循环中，并且也在身体的各个器官内以旁分泌方式发挥作用。虽然 RAS 被发现于全身的许多组织，我们已经证明大脑 RAS 的过度活跃足以导致血压、体液平衡和代谢调节的严重紊乱。我们已经确定介导每种表型的特定的、不同的信号传导机制。目前的提案将主要关注大脑 RAS 的代谢调节机制。根据我们的初步发现，我们假设大脑 RAS 通过以下方式刺激生热作用：两种机制。首先，通过激活交感神经系统，大脑 RAS 刺激棕色脂肪组织内的产热作用。其次，通过加压素介导的高血压，大脑 RAS 抑制循环 RAS。抑制循环 RAS 导致血管紧张素减少白色脂肪细胞和前脂肪细胞内的 AT2 受体信号传导，导致脂肪细胞形成增加棕色脂肪细胞，从而增加产热能力。这些机制共同发挥协同作用积极影响新陈代谢率。对这些机制的检查可能会导致识别代谢疾病的新治疗靶点。