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: 7477932
• 负责人: Eric Gerald Krause
• 金额: $ 4.96万
• 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/7477932
• 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）：高血压影响着大约 5000 万美国人，这种疾病的进展会显着增加心力衰竭和肾衰竭的风险。高血压的发生被认为部分是由于肾素血管紧张素系统（RAS）过度活跃，肾素血管紧张素系统是一种对于调节心血管功能和水矿物质平衡至关重要的内分泌系统。 RAS 的效应肽血管紧张素 II (ANGII) 介导对失血、钠缺乏和低血压的代偿反应。在外周，ANGII 通过与血管上的血管紧张素 1 型受体 (AT1R) 结合而引起血管收缩并促进 Na+ 重吸收。在大脑中，ANGII 与室周器官 (CVO) 中的 AT1R 结合，引发激素释放、交感神经流出以及水和钠消耗增加的变化。虽然人们对 ANGII 对脉管系统反应性和肾脏 Na+ 处理的影响了解很多，但控制 ANGII 反应的中心途径仍不清楚。先前的研究使用 AT1R 拮抗剂或脑损伤来检查 ANGII 的中枢反应，但这些方法有局限性。病变研究可以评估大脑区域的功能，但缺乏提供有关特定神经元表型信息的分辨率。相反，药理学操作允许评估神经元表型，但将药物限制在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。反义的施用改变了个体大脑区域内的特定神经元表型，从而允许评估该离散群体内的神经元的功能。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循环 ANGII 反应中的作用。具体来说，针对 AT1R 的反义药物将被注射到大鼠的特定 CVO 中。随后，我将检查对不同地增加循环 ANGII 的治疗的行为、内分泌和神经反应。这些结果将为了解特定大脑区域内 AT1R 的功能及其在调节循环 ANGII 反应中所发挥的作用提供有价值的见解，同时也为未来采用中央基因操作的研究奠定基础。