PPG-Genetic and Signaling Mechanisms in the Central Regulation of Blood Pressure

描述(由申请人提供)： 中枢神经系统在调节血压和体重方面起着重要作用，这些通路的异常可导致高血压和肥胖。有证据表明，人类原发性高血压的特征是神经体液机制的持续变化，这一证据现在非常令人信服。血压中枢调节(CRBP)PPG的长期目标和中心主题是识别和澄清导致高血压和肥胖相关高血压的基本机制，重点是中枢神经系统中的遗传和信号通路以及中枢血管紧张素和瘦素的作用。概念框架和总体假设是，包括高血压和肥胖相关高血压在内的心血管疾病涉及基本细胞过程的功能障碍，其中包括中枢神经系统的信号传递，导致神经体液机制的持续变化。研究计划通过检验以下假设从概念上促进我们对血压中枢调节的理解：1.脑内一种新形式的细胞内活性肾素在血管紧张素II的细胞内产生中起重要作用，并且是动脉血压中枢调节的关键决定因素。2.氧化还原介导的中枢神经系统关键回路中NFkB和AP-1的激活是血管依赖性高血压发病机制中的分子事件。3.下丘脑中瘦素受体的不同信号通路调节局部交感神经系统活动和动脉压的不同或选择性作用。4.中枢神经系统尤其是瘦素信号和/或神经元回路缺陷在Bardet-Biedl综合征的高血压和肥胖中起着重要的病理生理作用。该计划由四个项目和三个核心组成，充分利用了人类和小鼠遗传学、基因操纵模型的开发和表征、分子生物学和细胞信号、向大脑的定点基因转移、神经解剖学和高血压神经生理学方面的广泛专业知识。该项目的调查人员持续保持着出色的工作效率记录，并建立了项目和核心领导之间广泛合作的证据。事实上，每个项目的初步数据都来自高血压专科研究中心(SCOR)资助的前5年期间取得的概念进展和合作。

DESCRIPTION (provided by applicant): The central nervous system plays important roles in the regulation of blood pressure and body weight, and abnormalities in these pathways can cause both hypertension and obesity. Evidence that human essential hypertension is characterized by sustained alterations in neurohumoral mechanisms is now extremely compelling. The long term goal and central theme of the Central Regulation of Blood Pressure (CRBP) PPG is to identify and clarify fundamental mechanisms that contribute to hypertension and obesity-associated hypertension focusing on genetic and signaling pathways in the central nervous system and the role of central angiotensin and leptin. The conceptual framework and overall hypothesis is that cardiovascular diseases including hypertension and obesity-associated hypertension involve dysfunction of basic cellular processes, among them signaling in the central nervous system, causing sustained alterations in neurohumoral mechanisms. Studies are planned to conceptually advance our understanding of central regulation of blood pressure by testing the following hypotheses: 1. A novel form of intracellular active renin in the brain plays an important role in the intracellular generation of angiotensin II and is a critical determinant in the central regulation of arterial pressure. 2. Redox-mediated activation of NFkB and AP-1 in key circuits of the central nervous system are causative molecular events in the pathogenesis of Ang-ll-dependent hypertension. 3. The divergent signaling pathways of the leptin receptor in the hypothalamus regulate differential or selective effects on regional sympathetic nervous system activity and arterial pressure. 4. The central nervous system in particular defects in leptin signaling and/or neuronal circuits plays a major pathophysiological role in hypertension and obesity in Bardet-Biedl Syndrome. The program consists of four projects and three cores taking full advantage of a breadth of expertise in human and mouse genetics, development and characterization of genetically manipulated models, molecular biology and cell signaling, site-selective gene transfer to the brain, neuroanatomy, and hypertension neurophysiology. There is a sustained record of outstanding productivity by the investigators of this program and established evidence for extensive collaboration among the project and core leaders. Indeed, each of the projects derives its preliminary data from conceptual advances and collaborations forged during the previous 5-year term of Hypertension Specialized Center of Research (SCOR) Funding.