课题基金 / 基金详情

Involvement of the Brain Orexin System in Hypertension

Involvement of the Brain Orexin System in Hypertension
大脑食欲素系统与高血压的关系
批准号:
10047063
负责人:
Zhiying Shan
金额:
$45.9万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-08-11 至 2024-06-30

项目摘要

项目成果

Zhiying Shan的其他基金

相似基金

相关文献

中文摘要
翻译
点击翻译按钮获取中文摘要
英文摘要
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.
期刊论文(8)
专著(0)
科研奖励(0)
会议论文
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
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: --
作者: [Larson,RobertA, Chen,Xinqian, Gu,Mingjun, Shan,Zhiying, Chen,Qinghui]
通讯作者: Chen,Qinghui
DOI: 10.3389/fphys.2021.641331
发表时间: 2021
期刊: Frontiers in physiology
影响因子: 4
作者: [Bigalke JA, Gao H, Chen QH, Shan Z]
通讯作者: Shan Z
7
    Contribution of Orexin System to Hypertension
    海外基金