The Neural Mechanisms of Hypertension

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，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。涉及终板和室旁核（PVN）的中枢机制在SSH的发展中起着重要作用;特别是PVN中的血管紧张素II（Ang II）1型受体（AT 1 R）介导交感神经张力和血压（BP）升高，以响应高盐。肾素受体（PRR）是新近发现的肾素-血管紧张素系统（RAS）的一个组成部分。肾素或原肾素与PRR的结合促进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表达水平升高，在PVN的高血压的人类受试者，但这种升高的意义在高血压是未知的。我们的中心假设是，PRR在室旁核的表达升高，通过增加局部血管紧张素II的形成和增强细胞内MAPK信号的激活，有助于SSH的发病机制。为了验证我们的假设，我们已经获得了PRR-floxed小鼠产生的PRR条件性敲除小鼠模型（Nefh-PRRKO），通过繁殖PRR-floxed小鼠与表达Cre重组酶的小鼠在神经元特异性neuroadherent-H（Nefh）启动子的控制下。在本研究中，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。我们的目标是描绘PRR信号通路在SSH PVN中的功能重要性，以及导致SSH中PRR升高的表观遗传机制。1）确定PVN中的PRR激活是否介导SSH的发展。2)阐明室旁核中PRR介导的MAPK信号对SSH的贡献。3)确定SSH中PVN中PRR表达升高的机制。该研究将揭示PVN PRR在SSH中的作用，并阐明其潜在的信号转导机制。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SSH中PRR重要性的知识空白，并提供了一个新的治疗靶点。

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.