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，具有盐敏感高血压（SSH）占所有情况的51％。作为增强的交感神经活动（SNA）和血浆增加众所周知，加压素（AVP）在SSH的发展中起关键作用，我们建议一项研究以调查中枢Orexin系统的基础机制对SNA失调和AVP刺激的影响生产，希望阐明SSH发展的主要成分。大脑室室核（PVN）在控制SNA流出和AVP释放中起着至关重要的作用以及血浆钠浓度感测。 Orexin A是下丘脑神经元产生的神经肽具有许多功能，但新出现的证据表明，Orexin System也参与了血压调节（BP）和SNA。 Orexin A通过与Orexin 1受体（OX1R）结合而引起其作用和/或OREXIN 2受体（OX2R），对前者的亲和力较高。大脑中的Orexin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， Orexin受体拮抗作用降低了这些大鼠的BP，表明过度活跃的脑OREXIN受体有助于高bp。但是，奥毛蛋白受体在SSH的发展和发展中的影响尚未决定。我们在本应用程序中的初步数据表明，OX1R和AVP的表达极为乙酸脱氧皮质酮（DOCA） - 盐高血压大鼠的PVN增加，SSH的动物模型模仿人类醛固酮主义，这是一种在盐敏感患者中观察到的症状，甚至更具耐药性高血压个体。在正常的Sprague Dawley（SD）大鼠中，Orexin A的中央给药增加了 PVN AVP的表达和Orexin A在PVN中的显微注射会增加SNA流出。这增加了 SNA流出被OX1R拮抗剂预先管理而阻塞。此外，我们的初步数据显示使用遗传学方法降低PVN OX1R表达可显着降低PVN AVP的表达和防止DOCA盐大鼠的HTN发育。这些观察结果使我们假设该文档盐处理上调PVN Orexin信号传导，这又增加了SNA流出并刺激 AVP生产和发行，最终导致HTN。我们将使用普通的SD和Doca-Salt型号执行各种最先进的分子和生理研究以回答以下问题：（1）正常大鼠PVN中OX1R的长期过表达会导致HTN吗？（2）做 PVN OX1R的慢性敲低阻止SSH的发展？（3）发出OREXIN信号调节中央矿物皮质受体（MR）或脑肾素 - 血管紧张素系统（RAS）的作用， SSH开发发展中的两个知名参与者？这项研究的结果可能会提供 SSH和抗性HTN处理的新目标。最重要的是，我们将为研究生提供机会和本科生参加该研究项目。

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.