权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Central actions of angiotensin II in the control of fluid balance

血管紧张素 II 在控制体液平衡中的中枢作用

基本信息

批准号：
8386641
负责人：
Lori Marie Flanagan-Cato
金额：
$ 37.11万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-16 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386641
关键词：
Acetates Address Adrenal Cortex Hormones Adrenal Glands Aldosterone Angiotensin II Angiotensin II Receptor Animals Area Atherosclerosis Behavior Behavioral Behavioral Mechanisms Binding Biological Assay Biological Models Body Fluids Brain Brain region CRH gene Captopril Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell Culture Techniques Cell physiology Cells Contrast Media Corticosterone Counseling Coupled Deoxycorticosterone Desire for food Development Dexamethasone Diuretics Dose Drug Combinations EGF gene Ensure Epidermal Growth Factor Receptor Equilibrium Fluid Balance Foundations Functional disorder Furosemide GTP-Binding Proteins Genomics Heart failure Histologic Homeostasis Hormones Hydrolysis Hypertension Hypotension Hypothalamic structure Immunoblot Analysis Immunoblotting In Vitro Ingestion Injection of therapeutic agent Intake Lateral Ligands Link Liquid substance Literature Losartan MAPK1 gene MAPK3 gene MEKs Maps Mediating Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Mitogens Modeling Organ Pathway interactions Patients Peptides Pharmaceutical Preparations Phenotype Phosphatidylinositols Physiological Process Proteins Rat-1 Rattus Receptor Signaling Regulation Renal function Renin-Angiotensin System Reporting Research Role Sampling Signal Pathway Signal Transduction Site Sodium Sodium Chloride Steroids Structure of area postrema Subfornical Organ Testing Thirst Time Transactivation Water consumption analog base hypertension treatment hypocretin in vitro Model in vivo inhibitor/antagonist interest motivated behavior neurochemistry organum vasculosum of the lamina terminalis peptide hormone protein activation receptor research study response salt intake water drinking behavior

项目摘要

DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) is a focus of intense research because it has been strongly implicated in the development of cardiovascular disease. The active component of the RAS, the peptide hormone angiotensin II (AngII), is an important regulator of cardiovascular and body fluid homeostasis. Therefore, the receptors that respond to AngII and the cellular, genomic, and physiological actions initiated by AngII binding are actively studied in an effort to understand the foundation for the development of cardiovascular diseases, such as hypertension, atherosclerosis, and cardiac failure. Body fluid homeostasis, which is intricately connected with cardiovascular function, depends on the coordinated regulation of complementary physiological and behavioral mechanisms. The principle behaviors that ensure stability of volume and composition of the fluid matrix are water and salt intake. AngII is importantly involved in the control of these motivated behaviors. Adrenal steroids also further regulate the brain's responsivity to AngII, thereby modulating thirst and salt appetite. Because the regulation of sodium balance in all animals is a key aspect of body fluid homeostasis, control of sodium intake is an important point of emphasis in the treatment of hypertension. While all hypertensive patients are counseled to restrict their sodium intake, many have great difficulty in complying. Thus, an understanding of this behavior has important ramifications with respect to pathophysiology of hypertension and cardiovascular disease. The Type 1 (AT1) AngII receptor subtype is primarily responsible for the physiological and behavioral responses to this peptide. For the AT1 receptor, there is considerable literature on cell signaling mediated by G-protein activation. However, AT1 receptors are now also recognized to be linked to activation nontraditional signaling pathways, including activation of mitogen activated protein kinases (MAPK). Recently, we have demonstrated that AngII-induced salt appetite is initiated by MAPK activation and not the more traditional G- protein mediated signaling associated with AT1 receptors. In the present application, we propose to investigate the cellular and neuroanatomical mechanisms that subserve salt appetite by using various drug conditions to isolate different branches of AT1 receptor signaling: (1) AngII, which activates all signaling pathways; (2) the peptide Sar1,Ile4,Ile8-AngII, which activates only MAPK; and (3) AngII combined with a MEK inhibitor, which activates only the traditional G-protein mediated signaling. Using these drug combinations, we will address: (1) the cellular intermediary proteins that connect the AT1 receptor to MAPK signaling, (2) the role of AT1-R mediated MAPK activation under physiological states that induce salt appetite, (3) the neurocircuitry that is employed in the development of salt appetite, and (4) the cellular mechanisms that permit adrenal steroids to modulate salt appetite. The hormone angiotensin II is a focus of intense research because it has been strongly implicated in the development of cardiovascular disease. Of the many actions of this hormone within the body, angiotensin II is an important regulator of fluid balance by coordinating physiological actions, such as kidney and cardiovascular function, with the behaviors of water drinking and the ingestion of salt (sodium). Because the regulation of sodium balance in all animals is a key aspect of body fluid regulation, control of sodium intake is an important point of emphasis in the treatment of hypertension. While all hypertensive patients are counseled to restrict their sodium intake, many have great difficulty in complying. Thus, an understanding of this behavior has important ramifications with respect to the development of hypertension and cardiovascular disease.

描述（由申请人提供）：肾素-血管紧张素系统（RAS）是深入研究的焦点，因为它与心血管疾病的发展密切相关。 RAS 的活性成分肽激素血管紧张素 II (AngII) 是心血管和体液稳态的重要调节剂。因此，人们积极研究对 AngII 做出反应的受体以及由 AngII 结合引发的细胞、基因组和生理作用，以了解高血压、动脉粥样硬化和心力衰竭等心血管疾病发生的基础。体液稳态与心血管功能密切相关，取决于互补的生理和行为机制的协调调节。确保流体基质体积和成分稳定性的主要行为是水和盐的摄入。 AngII 重要地参与这些动机行为的控制。肾上腺类固醇还进一步调节大脑对 AngII 的反应，从而调节口渴和盐的食欲。由于所有动物钠平衡的调节是体液稳态的一个关键方面，因此控制钠摄入量是高血压治疗的一个重要重点。尽管建议所有高血压患者限制钠摄入量，但许多人很难遵守。因此，了解这种行为对于高血压和心血管疾病的病理生理学具有重要影响。 1 型 (AT1) AngII 受体亚型主要负责对该肽的生理和行为反应。对于 AT1 受体，有大量关于 G 蛋白激活介导的细胞信号传导的文献。然而，现在人们也认识到 AT1 受体与非传统信号通路的激活有关，包括丝裂原激活蛋白激酶 (MAPK) 的激活。最近，我们证明了 AngII 诱导的盐食欲是由 MAPK 激活启动的，而不是由与 AT1 受体相关的更传统的 G 蛋白介导的信号传导启动的。在本申请中，我们建议通过使用各种药物条件来分离AT1受体信号传导的不同分支来研究促进盐食欲的细胞和神经解剖学机制：（1）AngII，它激活所有信号传导途径； (2) 肽Sar1,Ile4,Ile8-AngII，仅激活MAPK； (3) AngII 与 MEK 抑制剂结合，仅激活传统的 G 蛋白介导的信号传导。使用这些药物组合，我们将解决：(1) 连接 AT1 受体与 MAPK 信号传导的细胞中间蛋白，(2) 在诱导盐食欲的生理状态下 AT1-R 介导的 MAPK 激活的作用，(3) 用于盐食欲发展的神经回路，以及 (4) 允许肾上腺类固醇调节盐食欲的细胞机制。血管紧张素 II 激素是深入研究的焦点，因为它与心血管疾病的发展密切相关。在这种激素在体内的多种作用中，血管紧张素 II 通过协调生理活动（例如肾脏和心血管功能）以及饮水和盐（钠）的摄入行为，是液体平衡的重要调节剂。由于所有动物钠平衡的调节是体液调节的一个关键方面，因此控制钠摄入量是高血压治疗的一个重要重点。尽管建议所有高血压患者限制钠摄入量，但许多人很难遵守。因此，了解这种行为对于高血压和心血管疾病的发展具有重要影响。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The role of the hypothalamic paraventricular nucleus and the organum vasculosum lateral terminalis in the control of sodium appetite in male rats.

下丘脑室旁核和终末外侧血管器在控制雄性大鼠钠食欲中的作用。

DOI：
10.1523/jneurosci.3979-13.2014
发表时间：
2014
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Grafe,LauraA;Takacs,AnneE;Yee,DanielK;Flanagan-Cato,LorettaM
通讯作者：
Flanagan-Cato,LorettaM

Differential effects of mineralocorticoid and angiotensin II on incentive and mesolimbic activity.