Central redox-signaling mechanisms in neurogenic hypertension

描述（由申请人提供）： 中枢神经系统（CNS）中的血管调节网络在维持动脉压中起着关键作用。这些回路中信号的失调是原发性高血压的关键因素。虽然血管紧张素-II（Ang-II）已成为驱动神经心血管功能障碍的主要原因，但关于Ang-II在CNS中的神经生理学知之甚少。最近的证据表明，活性氧（ROS）是血管紧张素Ⅱ高血压中枢神经系统核团中的关键分子。然而，心血管神经元中Ang-II诱导的ROS的精确来源和下游效应物尚不清楚。使用最近开发的分子工具，沿着最先进的分子成像和综合生理学评估，我们将测试以下假设：1）CNS中NAD（P）H氧化酶的失调激活是Ang-II神经源性高血压中ROS的来源，和2）心血管神经元中ROS介导的关键激酶和转录因子的激活是Ang-II高血压中的致病事件。使用靶向腺病毒递送短发夹干扰RNA至CNS，我们将选择性地抑制特定脑区域内NAD（P）H氧化酶同系物的表达，以剖析它们在中枢Ang-II血压调节中的不同作用。然后，我们将利用Cre/loxP系统限制基因消融的CaMKII特定的大脑区域，以确定这种激酶在神经源性高血压的功能意义。最后，为了确定氧化还原敏感性转录因子NF κ B和AP-1在Ang-II神经源性高血压中的作用，我们将利用生物发光成像来时空映射原发性高血压实验模型中活小鼠CNS核中这些转录因子的激活。虽然目前有数百万人患有原发性高血压，但这种疾病的确切原因尚不清楚。由于大脑对心血管功能具有如此强大的影响力，高血压主要是由于大脑中的心血管控制区域无法有效调节血压。因此，对血压调节所涉及的神经机制的完整理解有可能激发治疗这种疾病的新的治疗策略。

DESCRIPTION (provided by applicant): Cardiovascular-regulatory networks in the central nervous system (CNS) play a critical role in the maintenance of arterial pressure. Dysregulation of signaling in these circuits is a key factor in essential hypertension. Although angiotensin-ll (Ang-ll) has emerged as a primary culprit in driving neurocardiovascular dysfunction, little is known regarding the neurophysiology of Ang-ll in the CNS. Recent evidence has revealed that reactive oxygen species (ROS) are key molecules in CNS nuclei in Ang-ll hypertension. However, the precise sources and downstream effectors of Ang-ll-induced ROS in cardiovascular neurons are not known. Using recently developed molecular tools, along with state-of-the-art molecular imaging and integrated physiological assessments, we will test the following hypotheses: 1) dysregulated activation of NAD(P)H oxidase(s) in the CNS is the source of ROS in Ang-ll neurogenic hypertension, and 2) ROS-mediated activation of key kinases and transcription factors in cardiovascular neurons are causative events in Ang-ll hypertension. Using targeted adenoviral delivery of short hairpin interfering RNA to the CNS, we will selectively inhibit expression of NAD(P)H oxidase homologues within specific brain regions to dissect their differential roles in central Ang-ll blood pressure regulation. We will then utilize a Cre/loxP system to restrict genetic ablation of CaMKII to specific brain regions to determine the functional significance of this kinase in neurogenic hypertension. Lastly, to establish the role of the redox-sensitive transcription factors NFkB and AP-1 in Ang-ll neurogenic hypertension, we will utilize bioluminescence imaging to spatio-temporally map the activation of these transcription factors in CNS nuclei of living mice in an experimental model of essential hypertension. Although millions currently suffer from essential hypertension, the exact cause of this disease is not known. Since the brain exerts such a powerful influence over cardiovascular function, hypertension results largely from a failure of cardiovascular control regions in the brain to effectively regulate blood pressure. Thus, a complete understanding of the neural mechanisms involved in blood pressure regulation has the potential to inspire novel therapeutic strategies for the treatment of this disease.