Role of Redox-Mediated Activation of NFkappaB and AP-1 in Neurogenic Hypertension

氧化还原介导的 NFkappaB 和 AP-1 激活在神经源性高血压中的作用

• 批准号: 7643152
• 负责人: Robin L Davisson
• 金额: $ 48.41万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643152
• 关键词: Address; Angiopoietin-2; Angiotensin II; Angiotensinogen; Animals; Antioxidants; Automobile Driving; Autonomic Dysfunction; Bioluminescence; Blood Pressure; Brain; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Chronic; Disease; Dominant-Negative Mutation; Essential Hypertension; Event; Evolution; Functional disorder; Future; Gene Transfer; Genes; Genomics; Heart failure; Human; Hydrogen Peroxide; Hypertension; Image; Life; Ligands; Link; Long-Term Effects; Maps; Mediating; Modeling; Molecular; Mus; Mutation; Nerve; Nervous System Physiology; Nervous system structure; Neural Pathways; Neuraxis; Nuclear; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Physiological; Play; Production; Receptor Signaling; Renin; Research; Research Personnel; Robin bird; Role; Signal Transduction; Site; Superoxides; Suppressor Genes; Technology; Transcription Factor AP-1; Translating; Viral; Viral Genes; blood pressure regulation; in vivo; inhibitor/antagonist; kidney vascular structure; molecular imaging; neurogenic hypertension; novel; novel therapeutics; programs; prototype; transcription factor

DESCRIPTION (provided by applicant): Human essential hypertension is characterized by sustained increases in sympathetic nerve activity. Exacerbation of angiotensin II (Ang-ll) signaling in the CNS has emerged as a primary culprit driving this chronic neuro-cardiovascular dysfunction, although the underlying molecular substrates are poorly understood. Recently we discovered that redox signaling in the CNS plays a primary role in the long-term effects of Ang-ll on blood pressure and sympathetic outflow. Furthermore, our studies demonstrate that chronic oxidative stress in central cardiovascular pathways is involved in the pathogenesis of hypertension and heart failure. The molecular mechanisms by which excessive oxidant production translates into long-lasting effects on central neural pathways controlling blood pressure are unknown. One way that transient ligand/receptor signals such as Ang-ll are transformed into long-term genetic changes is through activation of specific inducible transcription factors. Nuclear factor kappaB (NFkappaB) and activator protein 1 (AP-1) are important redox-sensitive transcription factors that mediate lasting changes in CNS function. Our preliminary in vivo bioluminescence imaging studies reveal a dramatic bi-phasic activation profile of NFkappaB and AP-1 in the brain of mice during the evolution of systemic Ang-ll "slow-pressor" hypertension. Building on this and also extending our studies to other models of brain Ang-ll-dependent hypertension, we will address the overall hypothesis that redox-mediated activation of NFkappaB and AP-1 in key CNS nuclei is causative molecular events in the pathogenesis of neurogenic hypertension and related autonomic dysfunction. Using a combination of live animal molecular imaging for serial tracking of NF?B and AP-1 activation, brain site-specific viral delivery of oxidant scavenging and dominant-suppressor genes, and integrative cardiovascular physiology in mice, we will perform the following studies: Aim 1) Spatiotemporally map and quantify NFkappaB and AP-1 activation in CNS cardiovascular nuclei of mice with Ang-ll slow-pressor, renovascular (2K1C) and life-long (human renin/human angiotensinogen) hypertension; Aim 2) Dissect the role of superoxide and H2O2 in Ang-ll-stimulated induction of NFkappaB and AP-1 activity in central cardiovascular circuits; Aim 3) Determine the functional role of central NFkappaB and AP-1 activation in the pathogenesis of neurogenic hypertension and related neuro-cardiovascular sequelae. This research has the potential to fundamentally advance our understanding of mechanisms linking the nervous system with cardiovascular disease, and could have important implications for developing novel therapeutic strategies for neurogenic hypertension and related disorders. A further strength of this project is the combination of live animal molecular imaging and sophisticated physiological genomic strategies.

描述（由申请人提供）：人类基本高血压的特征是交感神经活动的持续增加。 CNS中血管紧张素II（ANG-LL）信号的加剧已成为驱动这种慢性神经性心血管功能障碍的主要罪魁祸首，尽管基本的分子底物知之甚少。最近，我们发现中枢神经系统中的氧化还原信号在Ang-LL对血压和交感神经流出的长期影响中起主要作用。此外，我们的研究表明，中央心血管途径中的慢性氧化应激与高血压和心力衰竭的发病机理有关。过量氧化剂产生对控制血压的中央神经途径的长期影响的分子机制尚不清楚。瞬时配体/受体信号（例如Ang-ll）转化为长期遗传变化的一种方法是激活特定的诱导转录因子。核因子Kappab（NFKAPPAB）和激活蛋白1（AP-1）是重要的氧化还原敏感转录因子，可介导CNS功能的持续变化。我们的初步体内生物发光成像研究揭示了在全身性ang-ll“慢速压力”高血压的演变过程中，NFKappab和AP-1在小鼠大脑中具有巨大的双重激活谱。在此基础上并将我们的研究扩展到其他脑Ang-ll依赖性高血压模型，我们将解决以下整体假设：在关键CNS核中，氧化还原介导的NFKAPPAB和AP-1的激活是神经生成性高血压和相关自主功能障碍的神经生成性高血压发病中的原因。 Using a combination of live animal molecular imaging for serial tracking of NF?B and AP-1 activation, brain site-specific viral delivery of oxidant scavenging and dominant-suppressor genes, and integrative cardiovascular physiology in mice, we will perform the following studies: Aim 1) Spatiotemporally map and quantify NFkappaB and AP-1 activation in CNS cardiovascular nuclei of mice with Ang-ll慢速，肾血管（2K1C）和终生（人类肾素/人血管紧张素原）高血压； AIM 2）剖析中央心血管回路中NFKappab和AP-1活性在Ang-Ll刺激诱导中的抗氧化物和H2O2的作用；目标3）确定中央NFKAPPAB和AP-1激活在神经源性高血压和相关神经性神经血管后遗症的发病机理中的功能作用。这项研究有可能从根本上促进我们对将神经系统与心血管疾病联系起来的机制的理解，并可能对为神经发生高血压和相关疾病开发新的治疗策略具有重要意义。该项目的另一个优势是活动物分子成像和复杂的生理基因组策略的结合。