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）：尽管最近在药物治疗和急性患者护理方面取得了进展，但心血管疾病（CVD）仍然是发病和死亡的主要原因。高血压是 CVD 的主要危险因素，导致 95% 的 CVD 死亡。盐敏感性高血压（SSH）是人类原发性高血压的一种主要形式。涉及终板和下丘脑室旁核（PVN）的中枢机制在 SSH 的发生发展中发挥着重要作用；特别是，PVN 中的血管紧张素 II (Ang II) 1 型受体 (AT1R) 会介导高盐引起的交感神经张力和血压 (BP) 升高。肾素（原）受体（PRR）是肾素-血管紧张素系统（RAS）的新发现成分。肾素或肾素原与 PRR 的结合促进 Ang II 形成并激活 Ang II 独立的丝裂原激活蛋白激酶 (MAPK) 信号。我们的初步数据显示，高血压人类受试者的 PVN 中 PRR 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 表达升高通过增加局部 Ang II 形成和增强细胞内 MAPK 信号激活，有助于 SSH 的发病机制。为了检验我们的假设，我们获得了 PRR-floxed 小鼠，通过将 PRR-floxed 小鼠与在神经元特异性神经丝-H (Nefh) 启动子控制下表达 Cre 重组酶的小鼠进行繁殖，产生了 PRR 条件敲除小鼠模型 (Nefh-PRRKO)。在本提案中，我们将在这些新型小鼠模型中诱导 SSH，并结合 PVN 微注射技术和最先进的遥测记录来检验我们的假设。我们的目标是描述 SSH 中 PVN 中 PRR 信号通路的功能重要性，以及导致 SSH 中 PRR 升高的表观遗传机制。将解决以下具体目标： 1) 确定 PVN 中的 PRR 激活是否介导 SSH 的发展。 2) 阐明PVN中PRR介导的MAPK信号传导对SSH的贡献。 3) 确定 SSH 中 PVN 中 PRR 表达升高的机制。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填补关于PRR在SSH中重要性的知识空白并提供新的治疗靶点，将对SSH的治疗产生显着的积极影响。