Involvement of the Brain Orexin System in Hypertension

大脑食欲素系统与高血压的关系

基本信息

批准号：
10047063
负责人：
Zhiying Shan
金额：
$ 45.9万
依托单位：
MICHIGAN TECHNOLOGICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-11 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047063
关键词：
Accounting Acetates Affinity Agonist Animal Model Area Arousal Attenuated Axon Binding Blood Blood Circulation Blood Pressure Body Fluids Brain Brain region Cardiovascular Diseases Cardiovascular system Chronic Data Deoxycorticosterone Development Disease Environment Genetic Heart Hypertrophy Hormone secretion Human Hyperaldosteronism Hypertension Hypothalamic structure Inbred SHR Rats Individual Injections Kidney Lead Lesion Life Style Modification Maintenance Mediating Methods Michigan Microinjections Mineralocorticoid Receptor Modeling Molecular Mus Nerve Neuraxis Neurons Neuropeptides Obesity Outcome Study Oxytocin Patients Peripheral Pharmaceutical Preparations Physiological Plasma Play Posterior Pituitary Gland Production Rattus Receptor Signaling Regulation Renin-Angiotensin System Research Research Personnel Research Project Grants Resistance Resistant Hypertension Rest Risk Factors Role Signal Transduction Site Sodium Sodium Chloride Spinal Cord Sprague-Dawley Rats Students Symptoms System Techniques Testing Transgenic Organisms United States Up-Regulation Vasopressins Wakefulness Work base blood pressure reduction blood pressure regulation cardiovascular risk factor economic implication graduate student human disease hypertension treatment hypocretin knock-down magnocellular novel strategies orexin 1 receptor orexin A orexin B receptor overexpression paraventricular nucleus parvocellular prevent programs receptor receptor expression salt intake salt sensitive salt sensitive hypertension social implication undergraduate student

项目摘要

SUMMARY Hypertension (HTN) is a major risk factor for cardiovascular disease, with salt sensitive hypertension (SSH) accounting for 51% of all cases. As augmented sympathetic nerve activity (SNA) and increased plasma vasopressin (AVP) are known to play key roles in the development of SSH, we propose a study to investigate the mechanism underlying central orexin system influence on both SNA dysregulation and stimulation of AVP production, in the hopes of elucidating a primary component to the development of SSH. The brain paraventricular nucleus (PVN) plays a crucial role in controlling SNA outflow and AVP release, as well as plasma sodium concentration sensing. Orexin A is a neuropeptide produced by hypothalamic neurons with numerous functions, but emerging evidence suggests that the orexin system is also involved in the regulation of blood pressure (BP) and SNA. Orexin A elicits its action by binding to orexin 1 receptor (OX1R) and/or orexin 2 receptor (OX2R), with a higher affinity for the former. Upregulation of orexin receptors in brain cardiovascular relevant regions including the PVN have been observed in several animal models of HTN, and orexin receptor antagonism lowers BP in those rats, suggesting overactive brain orexin receptors contribute to high BP. However, the impact of orexin receptor in the development and progression of SSH has not been determined. Our preliminary data in this application shows that expression of OX1R and AVP is dramatically increased in the PVN of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, an animal model of SSH mimicking human aldosteronism, a symptom observed in salt sensitive patients and even more so in resistant hypertensive individuals. In normal Sprague Dawley (SD) rats, central administration of orexin A increases PVN AVP expression, and microinjection of orexin A into the PVN increases SNA outflow. This increase in SNA outflow is blocked by pre-administration of an OX1R antagonist. In addition, our preliminary data shows that decreasing PVN OX1R expression using a genetic method markedly decreases PVN AVP expression and prevents HTN development in DOCA-salt rats. These observations have led us to hypothesize that DOCA- salt treatment upregulates PVN orexin signaling, which, in turn, increases SNA outflow and stimulates AVP production and release, ultimately resulting in HTN. We will use normal SD and DOCA-salt models to perform various state-of-the-art molecular and physiological studies to answer the following questions: (1) Does long-term overexpression of OX1R in the PVN of normal rats result in HTN? (2) Does chronic knockdown of the PVN OX1R prevent the development of SSH? (3) Does orexin signaling modulate the actions of central mineralocorticoid receptors (MR) or the brain renin-angiotensin system (RAS), two established players in the development of SSH development? The outcome of this study may provide a new target for both SSH and resistant HTN treatment. Most importantly, we will offer an opportunity for graduate and undergraduate students to participate in this research project.

概括高血压（HTN）是心血管疾病的主要危险因素，其中盐敏感性高血压（SSH）占全部病例的51%。随着交感神经活动（SNA）增强和血浆浓度增加已知加压素 (AVP) 在 SSH 的发展中发挥关键作用，我们提出一项研究来调查中枢食欲素系统影响 SNA 失调和 AVP 刺激的机制生产，希望阐明 SSH 开发的主要组成部分。脑室旁核 (PVN) 在控制 SNA 流出和 AVP 释放方面起着至关重要的作用，以及血浆钠浓度传感。食欲素 A 是下丘脑神经元产生的神经肽具有多种功能，但新的证据表明食欲素系统也参与血压 (BP) 和 SNA 的调节。食欲素 A 通过与食欲素 1 受体 (OX1R) 结合而发挥作用和/或食欲素 2 受体 (OX2R)，对前者具有更高的亲和力。大脑中食欲素受体的上调在几种 HTN 动物模型中观察到包括 PVN 在内的心血管相关区域，并且食欲素受体拮抗作用可降低这些大鼠的血压，表明大脑食欲素受体过度活跃有助于高血压。然而，食欲素受体在 SSH 发生和进展中的影响尚未明确。决定。我们在此应用中的初步数据表明 OX1R 和 AVP 的表达显着增加醋酸脱氧皮质酮 (DOCA) 盐高血压大鼠 (SSH 动物模型) 的 PVN 增加模仿人类醛固酮增多症，这是一种在盐敏感患者中观察到的症状，在耐药患者中更是如此高血压人群。在正常 Sprague Dawley (SD) 大鼠中，中枢施用的食欲素 A 增加 PVN AVP 表达以及将食欲素 A 显微注射到 PVN 中会增加 SNA 流出。这一增加预施用 OX1R 拮抗剂可阻断 SNA 流出。此外，我们的初步数据显示使用遗传方法降低 PVN OX1R 表达可显着降低 PVN AVP 表达，并且防止 DOCA 盐大鼠发生 HTN。这些观察使我们推测 DOCA- 盐处理上调 PVN 食欲素信号传导，进而增加 SNA 流出并刺激 AVP的产生和发布，最终产生HTN。我们将使用普通 SD 和 DOCA 盐模型进行各种最先进的分子和生理学研究来回答以下问题：（1）正常大鼠PVN长期过度表达OX1R会导致高血压吗？ (2) 是否 PVN OX1R 的慢性敲低会阻止 SSH 的发展吗？ (3) 食欲素信号传导调节中枢盐皮质激素受体（MR）或大脑肾素-血管紧张素系统（RAS）的作用， SSH开发中的两个老牌玩家？这项研究的结果可能提供一个 SSH 和耐药 HTN 治疗的新目标。最重要的是，我们将为毕业生提供一个机会和本科生参与该研究项目。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TNFα Triggers an Augmented Inflammatory Response in Brain Neurons from Dahl Salt-Sensitive Rats Compared with Normal Sprague Dawley Rats.

DOI：
10.1007/s10571-021-01056-9
发表时间：
2022-08
期刊：
Cellular and molecular neurobiology
影响因子：
4
作者：
Gao H;Bigalke J;Jiang E;Fan Y;Chen B;Chen QH;Shan Z
通讯作者：
Shan Z

Conductive 3D nano-biohybrid systems based on densified carbon nanotube forests and living cells.

DOI：
10.1557/s43578-023-01163-x
发表时间：
2024
期刊：
JOURNAL OF MATERIALS RESEARCH
影响因子：
2.7
作者：
Bagheri, Roya;Ball, Alicia K.;Kasraie, Masoud;Chandra, Aparna;Chen, Xinqian;Miskioglu, Ibrahim;Shan, Zhiying;Abadi, Parisa Pour Shahid Saeed
通讯作者：
Abadi, Parisa Pour Shahid Saeed

SK Channel Dysfunction in the Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Dahl Salt-Sensitive Rats.

下丘脑室旁核 SK 通道功能障碍导致 Dahl 盐敏感大鼠的交感神经兴奋。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Larson,RobertA;Chen,Xinqian;Gu,Mingjun;Shan,Zhiying;Chen,Qinghui
通讯作者：
Chen,Qinghui

Activation of Orexin 1 Receptors in the Paraventricular Nucleus Contributes to the Development of Deoxycorticosterone Acetate-Salt Hypertension Through Regulation of Vasopressin.