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。终板和室旁核（PVN）参与的中枢机制在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（AT 1 R）介导交感神经张力和血压（BP）响应于高盐的增加。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形成，并且还激活Ang II非依赖性促分裂原活化蛋白激酶（MAPK）信号传导。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，然而，在高血压期间这种升高的意义是未知的。我们的中心假设是，高血压刺激增加PRR的表达表观遗传在PVN，促进局部血管紧张素II的形成，通过激活的原肾素，导致交感兴奋和高血压。为了验证这一假设，我们将应用PVN显微注射和遥测记录技术的实验SSH的小鼠模型。这些研究的核心是PRR条件性敲除小鼠品系（Nefh-PRRKO），我们通过在我们实验室生产的神经元特异性神经元特异性-H（Nefh）启动子控制下表达Cre重组酶的小鼠与PRR-floxed小鼠交配产生。我们的目标是描绘PRR信号通路在高血压PVN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PVN中PRR激活介导高血压发展的假设。2)验证PRR下游的丝裂原活化蛋白激酶信号传导对于高血压的发展是强制性的这一假设。3)确定高血压PVN中PRR表达升高的表观遗传机制。这项研究将揭示PVN PRR在高血压中的作用，并阐明潜在的信号传导机制。通过确立PRR在高血压中的重要性并描述新的治疗靶点，这些研究将对心血管生物学产生直接影响，并可能为开发新一类抗高血压药物打开大门。

 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.