The effect of AT1R antisense on centrally-mediated responses to angiotension II

AT1R 反义对中枢介导的血管紧张素 II 反应的影响

• 批准号: 7336444
• 负责人: Eric Gerald Krause
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336444
• 关键词: Address; Affect; Aftercare; American; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensins; Appetitive Behavior; Behavioral; Binding; Blood Vessels; Brain; Brain region; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Consumption; Corticosterone; Development; Disease Progression; Endocrine; Endocrine system; Equilibrium; Evaluation; Feeding behaviors; Fluid Balance; Foundations; Future; Gene Targeting; Heart; Hemorrhage; Hormonal; Hormones; Hypertension; Hypotension; Individual; Intake; Kidney; Kidney Failure; Lesion; Liquid substance; Measures; Mediating; Methodology; Methods; Neurons; Organ; Pathway interactions; Peptides; Pharmaceutical Preparations; Phenotype; Plasma; Population; Rattus; Receptor, Angiotensin, Type 1; Reflex action; Regulation; Renin-Angiotensin System; Resolution; Risk; Role; Role playing therapy; Sodium; Subfamily lentivirinae; Vasopressins; Water; genetic manipulation; insight; receptor; relating to nervous system; research study; response; vasoconstriction

DESCRIPTION (provided by applicant): Hypertension affects approximately 50 million Americans and progression of this disease significantly increases risks for heart and renal failure. The development of hypertension is believed to be due, in part, to overactivity of the Renin-Angiotensin-System (RAS), an endocrine system critical for the regulation of cardiovascular function and hydromineral balance. The effector peptide of the RAS, angiotensin II (ANGII), mediates compensatory responses to blood loss, sodium depletion, and hypotension. In the periphery, ANGII elicits vasoconstriction and promotes Na+ reabsorption by binding to angiotensin type 1 receptors (AT1R) on blood vessels. In the brain, ANGII binds to AT1R in circumventricular organs (CVOs) to initiate changes in hormone release, sympathetic outflow, and increased water and sodium consumption. While much is known about the effects of ANGII on vasculature reactivity and renal Na+ handling, the central pathways governing responses to ANGII remain unclear. Previous studies have used AT1R antagonists or brain lesions to examine central responses to ANGII, but these approaches have limitations. Lesion studies allow for the evaluation of the function of brain regions, but lack the resolution to provide information about specific neuronal phenotypes. Conversely, pharmacological manipulations allow evaluation of neuronal phenotypes, but limiting the administration of the drug to discrete brain regions is problematic. An alternative method is to use antisense methodology to inhibit the expression of target genes in discrete brain regions. Administration of antisense alters specific neuronal phenotypes within individual brain regions, thereby allowing evaluation of the function of neurons within this discrete population. For the proposed experiments, antisense will be used to inhibit the expression of the AT1R in specific brain nuclei, thereby allowing evaluation of the role of these receptors in mediating responses to circulating ANGII. Specifically, antisense targeted against the AT1R will be injected into specific CVOs of rats. Subsequently, I will examine behavioral, endocrine, and neural responses to treatments that differentially increase circulating ANGII. The results will provide valuable insight to the function of AT1R within specific brain regions and the role they play in mediating responses to circulating ANGII, while also serving as a foundation for future studies employing central genetic manipulations.

描述（由申请人提供）：高血压影响约5000万美国人，这种疾病的进展显着增加了心脏和肾衰竭的风险。据信高血压的发展部分归因于肾素 - 血管紧张素系统（RAS）的过度活动，这是一种对调节心血管功能和氢化层平衡至关重要的内分泌系统。 RAS的效应肽，血管紧张素II（Angii）介导了对失血，钠耗竭和低血压的补偿性反应。在外围，血管群引起血管收缩并通过与血管上的血管紧张素1受体（AT1R）结合来促进Na+重吸收。在大脑中，AngII与围室器官（CVO）中的ATII结合，以启动激素释放的变化，交感神经流出以及增加的水和钠消耗。尽管对Angii对脉管反应性和肾脏NA+处理的影响知之甚少，但管理对Angii的反应的中心途径尚不清楚。先前的研究使用了AT1R拮抗剂或脑病变来检查对ANGII的中心反应，但是这些方法有局限性。病变研究允许评估大脑区域的功能，但缺乏提供有关特定神经元表型的信息的解决方案。相反，药理操作允许评估神经元表型，但是将药物的给药限制为离散的大脑区域是有问题的。另一种方法是使用反义方法来抑制离散大脑区域中靶基因的表达。反义的给药会改变单个大脑区域内的特定神经元表型，从而评估该离散人群中神经元功能。对于拟议的实验，反义将用于抑制特定脑核中AT1R的表达，从而评估这些受体在介导对循环ANGII的介导反应中的作用。具体而言，针对AT1R的反义将被注入大鼠的特定CVO中。随后，我将检查对差异增加循环ANGII的治疗的行为，内分泌和神经反应。该结果将为特定大脑区域内AT1R的功能以及它们在调解对循环AngII的反应中所起的作用提供宝贵的见解，同时也是采用主要遗传操作的未来研究的基础。