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

PPG-血压中枢调节的遗传和信号机制

• 批准号: 7433915
• 负责人: Curt Daniel Sigmund
• 金额: $ 199.93万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433915
• 关键词: PPG; Genetic; Signaling; Mechanisms; Central

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.

描述（由申请人提供）： 中枢神经系统在调节血压和体重的调节中起着重要作用，在这些途径中异常会导致高血压和肥胖症。现在，人类本质高血压的特征是神经肿瘤机制的持续改变的证据现在非常引人注目。血压中央调节（CRBP）PPG的长期目标和中心主题是识别和阐明基本机制，这些机制有助于高血压和肥胖相关的高血压，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的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中的信号传导，从而导致神经肿瘤机制的持续改变。计划通过测试以下假设来概念地从概念上提高我们对血压中心调节的理解：1。大脑中细胞内活性肾素的一种新型形式在细胞内血管紧张素II中起重要作用，并且在动脉压的中央调节中是一个关键的决定因素。 2。氧化还原介导的NFKB和AP-1在中枢神经系统的关键回路中的激活是Ang-LL依赖性高血压发病机理中的致病分子事件。 3。下丘脑中瘦素受体的发散信号传导途径调节对区域交感神经系统活性和动脉压的差异或选择性影响。 4。瘦素信号传导和/或神经元回路中的中枢神经系统在Bardet-Biedl综合征的高血压和肥胖症中起主要的病理生理作用。该程序由四个项目和三个核心组成，它充分利用了人类和小鼠遗传学的广度，遗传操纵模型的发展和表征，分子生物学和细胞信号传导，现场选择性基因转移到大脑，神经解剖学以及高血压神经生理学。该计划的调查人员持续记录了持续的出色生产力，并为该项目和核心领导者之间的广泛合作提供了证据。实际上，每个项目都从在高血压专业研究中心（SCOR）资金期间锻造的概念进步和合作中得出了初步数据。