The Neural Mechanisms of Hypertension

高血压的神经机制

• 批准号: 8986722
• 负责人: Yumei Feng Earley
• 金额: $ 36.85万
• 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/8986722
• 关键词: Acetates; Acute; Address; Affect; Angiotensin II; Angiotensinogen; Antihypertensive Agents; Autopsy; Binding; Biological Neural Networks; Biology; Blood Pressure; Brain; Breeding; Cardiovascular Diseases; Cardiovascular system; Categories; Cessation of life; Chromatin; Complex; Data; Dependovirus; Development; Disease; Enzymes; Epigenetic Process; Essential Hypertension; Event; Generations; Goals; Health; Heart Rate; Histones; Human; Hyperactive behavior; Hypertension; Hypothalamic structure; Inactive Renin; Indium; Integral Membrane Protein; Kidney; Knock-in; Knock-out; Knockout Mice; Laboratories; Lamina Terminalis; LoxP-flanked allele; Lysine; MAPK3 gene; Mediating; Microinjections; Mitogen-Activated Protein Kinases; Modeling; Modification; Morbidity - disease rate; Mouse Strains; Mus; Mutant Strains Mice; Neurofilament-H; Neurons; Pathogenesis; Patient Care; Patients; Peptides; Peptidyl-Dipeptidase A; Physiological; Play; RNA; Receptor Activation; Receptor Signaling; Receptor, Angiotensin, Type 1; Recombinant adeno-associated virus (rAAV); Renin; Renin-Angiotensin System; Reporting; Research; Risk Factors; Role; Sampling; Signal Pathway; Signal Transduction; Sodium Chloride; Stimulus; Techniques; Telemetry; Testing; United States; Up-Regulation; Vasopressins; blood pressure regulation; chromatin immunoprecipitation; hormone regulation; human subject; hypertension treatment; insight; mortality; mouse model; neuromechanism; new therapeutic target; novel; novel strategies; paraventricular nucleus; prevent; promoter; receptor; receptor expression; receptor upregulation; recombinase; response; salt sensitive hypertension; small hairpin RNA

 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) remains 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. Central mechanisms involving the lamina terminalis and the paraventricular nucleus (PVN) of the hypothalamus play an important role in the development of SSH. In particular, the angiotensin II (Ang II) type 1 receptor (AT1R) in the PVN mediates increases 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 the PRR promotes Ang II formation and also activates Ang II- independent mitogen-activated protein kinase (MAPK) signaling. Our preliminary data show that PRR expression levels are elevated in the PVN of hypertensive human subjects; however, the significance of this elevation during hypertension is not known. Our central hypothesis is that hypertensive stimuli increase PRR expression epigenetically in the PVN, which promotes local Ang II formation through activation of prorenin, leading to sympathoexcitation and hypertension. To test this hypothesis, we will apply PVN microinjection and telemetry recording techniques to a mouse model of experimentally SSH. Central to these studies is a PRR conditional knockout mouse strain (Nefh-PRRKO) that we generated by breeding mice expressing Cre recombinase under the control of a neuron-specific neurofilament-H (Nefh) promoter, produced in our laboratory, with PRR-floxed mice. Our objectives are to delineate the functional importance of PRR signaling pathways in the PVN in hypertension and elucidate the epigenetic mechanisms leading to PRR elevation. The following specific aims will be addressed: 1) Test the hypothesis that PRR activation in the PVN mediates the development of hypertension. 2) Test the hypothesis that mitogen-activated protein kinase signaling downstream of the PRR is mandatory for the development of hypertension. 3) Identify the epigenetic mechanisms responsible for elevated PRR expression in the PVN in hypertension. The proposed research will uncover the role of the PVN PRR in hypertension and elucidate the underlying signaling mechanisms. By establishing the importance of the PRR in hypertension and describing novel therapeutic targets, these studies will have a direct impact on cardiovascular biology and may open the door to the development of a new category of antihypertensive drugs.

 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) 仍然是发病率和死亡率的主要原因。高血压是 CVD 的主要危险因素，并且导致 95% 的 CVD 死亡。敏感性高血压（SSH）是人类原发性高血压的一种主要形式，涉及下丘脑终板和室旁核（PVN）的中枢机制在高血压的发生中发挥重要作用。特别是，PVN 中的血管紧张素 II (Ang II) 1 型受体 (AT1R) 会因高盐而导致交感神经紧张和血压 (BP) 升高。肾素 (PRR) 受体 (PRR) 是一种新的受体。发现了肾素-血管紧张素系统 (RAS) 的组成部分，肾素或肾素原与 PRR 的结合可促进 Ang II 形成，并激活 Ang II 独立的丝裂原激活蛋白激酶 (MAPK)。我们的初步数据表明，高血压患者的 PVN 中 PRR 表达水平升高；然而，高血压期间这种升高的意义尚不清楚，我们的中心假设是高血压刺激会增加 PVN 中的 PRR 表达，从而促进 PRR 的表达。通过激活肾素原形成局部血管紧张素II，导致交感神经兴奋和高血压。为了检验这一假设，我们将PVN显微注射和遥测记录技术应用于实验性SSH小鼠模型。 PRR 条件敲除小鼠品系 (Nefh-PRRKO)，是我们通过在神经元特异性神经丝 H (Nefh) 启动子控制下繁殖表达 Cre 重组酶的小鼠而产生的，该小鼠是在我们实验室生产的，我们的目标是。描述高血压中 PVN 中 PRR 信号通路的功能重要性，并阐明导致 PRR 升高的表观遗传机制。将解决以下具体目标：1）检验以下假设。 PVN 中的 PRR 激活介导高血压的发展。 2) 检验 PRR 下游的丝裂原激活蛋白激酶信号传导对于高血压的发展是必需的这一假设。 3) 确定导致 PVN 高血压中 PRR 表达升高的表观遗传机制。拟议的研究将揭示 PVN PRR 在高血压中的作用，并通过确定 PRR 在高血压中的重要性并描述新的治疗靶点，阐明潜在的信号机制，这些研究将对心血管生物学产生直接影响。并可能为开发一类新的抗高血压药物打开大门。