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.

心血管疾病和代谢性疾病在全球的Tiuman Hiealth上迅速增长。目前，美国大约三分之一的成年人口在临床上肥胖，一个第三次表现出持续的高血压。表现出肥胖和高血压。总体而言，经济，社会，心理和生产力负担心血管疾病和代谢疾病每年花费大约四分之一。一种激素系统涉及代谢和心血管功能的调节是肾素 - 血管紧张素系统（RAS）。该系统作为经典激素系统存在于流通中，并且同样在人体的个体孔中，以旁分泌方式起作用。当拉斯发现整个身体的许多组织，我们已经证明了大脑Ras的多动症足以足以导致血压，液体平衡和代谢调节的严重干扰。我们已经确定了介导每个表型的特定，不同的信号传导机制。当前的提案将狭窄地关注大脑RAS代谢调节的机制。在我们的初步发现的指导下，我们假设大脑Ras刺激了通过两种机制。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热发生。其次，通过加压素介导的高血压，大脑 RAS抑制了循环的RA。抑制循环RA会导致血管紧张素减少白色脂肪细胞和前脂肪细胞中的AT2受体信号传导，这导致形成增加棕色脂肪细胞，从而增加了热能力。这些机制共同起作用积极影响代谢率。检查这些机制可能会导致识别新型治疗靶标的代谢疾病。