Central redox-signaling mechanisms in neurogenic hypertension

点击翻译按钮获取中文摘要

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.