Central Angiotensin receptors and teh neural control of homeostasis

中枢血管紧张素受体和稳态的神经控制

基本信息

批准号：
8328924
负责人：
Eric Gerald Krause
金额：
$ 24.63万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-09 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8328924
关键词：
Address Adrenal Glands Affect American Angiotensin II Angiotensin Receptor Angiotensins Anxiety Anxiety Disorders Base of the Brain Behavior Behavioral Biological Blood Pressure Brain Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cause of Death Chronic Chronic stress Clinical Research Corticosterone Corticotropin Corticotropin-Releasing Hormone Disease Disease Progression Exposure to Heart Rate Homeostasis Hypertension Hypothalamic structure Instruction Laboratory Rat Laboratory mice Link Mediator of activation protein Mental Health Mental disorders Mood Disorders Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Patients Peptides Phase Pituitary Gland Rattus Receptor, Angiotensin, Type 1 Renin-Angiotensin System Reporting Research Research Design Risk Severities Stress Subfamily lentivirinae Subfornical Organ System Systems Development Testing Therapeutic Thymus Gland United States Up-Regulation Weight biological adaptation to stress biological systems cardiovascular disorder risk clinical application feeding heart rate variability hypothalamic-pituitary-adrenal axis improved neuroregulation novel paraventricular nucleus pressure prevent receptor receptor expression research study response

项目摘要

Hypertension affects approximately 50 million Americans and progression of this disease significantly increases risk for cardiovascular disease. Recent clinical studies demonstrate that hypertension also is associated with mental health disorders. Specifically, hypertension increases the risk of anxiety disorders, and inversely, anxiety disorders predict the risk and severity of hypertension and cardiovascuiar disease. While the onset of hypertension is attributed to over activity ofthe renin-angiotensin-system (RAS), the development of anxiety is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The effector peptide ofthe RAS, angiotensin II (ANGII), exerts the majority of its biological effects via activation of angiotensin type 1 receptors (AT1R). Interestingly, AT1R are expressed throughout the HPA axis and emerging evidence has implicated ANGII as an important mediator of the stress response. Chronic exposure to stress up-regulates the HPA axis and RAS, thereby negatively affecting cardiovascular and mental health. Given that chronic stress similarly up-regulates the HPA axis and the RAS, it is likely that an Interaction between these systems underlies the effects that chronic stress has on mental health and cardiovascular function. Because repeated stress increases AT1R expression in the brain, it is likely that chronic stress potentiates the influence of ANGII on the HPA axis, thereby inducing cardiovascular and affective disorders. Collectively, these studies suggest that therapies targeting the RAS may influence the onset of brain-basied disorders like anxiety, and therefore, it is important to understand the central angiotensinergic pathways that influence responses to stress. Accordingly, the proposed experiments will to inhibit ATI R in the brains of laboratory rats and mice to detemriine the contribution of these receptors to the cardiovascular, HPA and behavioral responses to chronic exposure to stress. These studies are designed to test the overall hypothesis that inhibition of AT1R in the brain will limit stress responding and alleviate the deleterious consequences of stress related illnesses.

高血压影响着大约 5000 万美国人，并且这种疾病的进展显着增加患心血管疾病的风险。最近的临床研究表明，高血压也与精神健康障碍有关。具体来说，高血压会增加患焦虑症的风险，相反，焦虑症可以预测高血压和心血管疾病的风险和严重程度。虽然高血压的发病是由于肾素血管紧张素系统 (RAS) 过度活动所致，焦虑的发生与下丘脑-垂体-肾上腺（HPA）轴的失调有关。 RAS 的效应肽血管紧张素 II (ANGII) 通过以下途径发挥其大部分生物学作用： 1 型血管紧张素受体 (AT1R) 的激活。有趣的是，AT1R 在整个 HPA 中表达轴和新出现的证据表明 ANGII 是应激反应的重要调节因子。慢性的暴露于压力会上调 HPA 轴和 RAS，从而对心血管和心血管系统产生负面影响心理健康。鉴于慢性压力同样会上调 HPA 轴和 RAS，因此很可能这些系统之间的相互作用是慢性压力对心理健康和健康产生影响的基础。心血管功能。由于反复的压力会增加大脑中 AT1R 的表达，因此很可能慢性应激会增强 ANGII 对 HPA 轴的影响，从而诱发心血管疾病情感障碍。总的来说，这些研究表明针对 RAS 的治疗可能会影响焦虑等脑部疾病的发作，因此了解中枢神经系统非常重要影响应激反应的血管紧张素能途径。因此，拟议的实验将抑制实验室大鼠和小鼠大脑中的 ATI R，以确定这些受体对心血管、HPA 和对长期压力的行为反应。这些研究旨在检验总体假设，即抑制大脑中的 AT1R 将限制压力反应并减轻压力压力相关疾病的有害后果。