The Neural Mechanisms of Hypertension

高血压的神经机制

• 批准号: 9061371
• 负责人: Yumei Feng Earley
• 金额: $ 25.61万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9061371
• 关键词: Acetates; Acute; Address; Affect; Angiotensin II; Angiotensin II Receptor; Antihypertensive Agents; Attenuated; Binding; Biological Neural Networks; Blood Pressure; Brain; Breeding; Cardiovascular Diseases; Cessation of life; Chromatin; Complex; Cyclic AMP-Responsive DNA-Binding Protein; DOCA; Data; Development; Epigenetic Process; Essential Hypertension; Genetically Engineered Mouse; Health; Histones; Human; Hypertension; Hypothalamic structure; Inactive Renin; Injection of therapeutic agent; Kidney; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Lamina Terminalis; Lysine; Mediating; Mitogen-Activated Protein Kinases; Modeling; Morbidity - disease rate; Mus; Neurofilament-H; Neurons; Pathogenesis; Patient Care; Patients; Phosphorylation; Play; Protein Inhibition; Receptor Activation; Receptor Signaling; Receptor, Angiotensin, Type 1; Recombinant adeno-associated virus (rAAV); Renin; Renin-Angiotensin System; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Sodium Chloride; Subfornical Organ; Techniques; Telemetry; Testing; United States; Up-Regulation; attenuation; blood pressure regulation; cytokine; histone modification; human subject; mortality; mouse model; neuromechanism; new therapeutic target; novel; paraventricular nucleus; prevent; promoter; protein activation; receptor; receptor expression; recombinase; relating to nervous system; response; restoration; salt sensitive hypertension; small hairpin RNA

DESCRIPTION (provided by applicant): Cardiovascular diseases (CVD) remain a leading cause of morbidity and mortality despite recent advances in pharmacological therapy and acute patient care. Hypertension is the major risk factor for CVD and contributes to 95% of CVD deaths. Salt-sensitive hypertension (SSH) is a major form of human primary hypertension. The central mechanisms involving the lamina terminalis and the paraventricular nucleus of the hypothalamus (PVN) play an important role in the development of SSH; in particular, the angiotensin II (Ang II) type 1 receptor (AT1R) in the PVN mediates elevation in sympathetic tone and blood pressure (BP) in response to high salt. The (pro)renin receptor (PRR) is a newly discovered component of the renin-angiotensin system (RAS). Binding of renin or prorenin to PRR promotes Ang II formation and activates Ang II-independent mitogen-activated protein kinases (MAPK) signals. Our preliminary data show that PRR expression levels are elevated in the PVN of hypertensive human subjects, but the significance of this elevation during hypertension is not known. Our central hypothesis is that elevated PRR expression in the PVN contributes to the pathogenesis of SSH by increasing local Ang II formation and enhancing the intracellular MAPK signal activation. To test our hypothesis, we have obtained PRR-floxed mice generated a PRR conditional knockout mouse model (Nefh-PRRKO) by breeding PRR-floxed mice with mice expressing Cre recombinase under the control of neuron-specific neurofilament-H (Nefh) promoter. In this proposal, we will induce SSH in these novel mouse models, combined with PVN micro-injection technique and state-of-the-art telemetry recording to test our hypothesis. Our objective is to delineate the functional importance of PRR signaling pathways in the PVN in SSH, and the epigenetic mechanisms leading to PRR elevation in SSH. The following specific aims will be addressed: 1) Determine if PRR activation in the PVN mediates the development of SSH. 2) Elucidate the contribution of PRR-mediated MAPK signaling in the PVN to SSH. 3) Identify the mechanisms responsible for elevated PRR expression in the PVN in SSH. The proposed research will uncover the role of PVN PRR in SSH and elucidate the underlying signaling mechanisms. The successful completion of these studies will have a significant positive impact on the treatment of SSH by filling the knowledge gap of the importance PRR in SSH and providing a novel therapeutic target.

描述(由申请人提供)：心血管疾病(CVD)仍然是发病率和死亡率的主要原因，尽管最近在药物治疗和急性患者护理方面取得了进展。高血压是心血管疾病的主要危险因素，占心血管疾病死亡人数的95%。盐敏性高血压(SSH)是人类原发性高血压的一种主要形式。终板和下丘脑室旁核(PVN)的中枢机制在SSH的发生发展中起重要作用，特别是PVN中的血管紧张素II(Ang II)1型受体(AT1R)介导交感神经张力和血压(BP)对高盐的反应。肾素受体(PRR)是新发现的肾素-血管紧张素系统(RAS)的组成部分。肾素或原肾素与PRR结合可促进Ang II的形成，并激活Ang II非依赖性丝裂原活化蛋白激酶(MAPK)信号。我们的初步数据显示，PRR在高血压受试者的PVN中的表达水平升高，但这种升高在高血压期间的意义尚不清楚。我们的中心假设是，PVN中PRR的高表达通过增加局部Ang II的形成和增强细胞内MAPK信号的激活而参与SSH的发病。为了验证我们的假设，我们通过在神经元特异性神经细丝-H(Nefh)启动子的控制下将表达Cre重组酶的PRR-FLOL小鼠与PRR-FLOL小鼠进行饲养，获得了产生PRR条件性基因敲除小鼠的PRR-FLOL小鼠模型(NefH-PRRKO)。在这个方案中，我们将在这些新的小鼠模型中诱导SSH，结合PVN显微注射技术和最先进的遥测记录来验证我们的假设。我们的目标是阐明在SSH的PVN中PRR信号通路的功能重要性，以及导致SSH中PRR升高的表观遗传学机制。将解决以下具体目标：1)确定PVN中PRR的激活是否参与SSH的发生。2)阐明PRR介导的下丘脑室旁核MAPK信号对SSH的作用。3)明确SSH时PVN中PRR表达升高的机制。这项拟议的研究将揭示PVN PRR在SSH中的作用并阐明潜在的信号机制。这些研究的成功完成将对SSH的治疗产生重大的积极影响，填补了对SSH中PRR重要性的认识空白，并提供了一个新的治疗靶点。