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）： 中枢神经系统在血压和体重的调节中起着重要的作用，这些通路的异常可能导致高血压和肥胖。人类原发性高血压以神经体液机制的持续改变为特征的证据现在非常引人注目。血压中枢调节（CRBP）PPG的长期目标和中心主题是识别和阐明导致高血压和肥胖相关高血压的基本机制，重点关注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，心血管疾病包括高血压和肥胖相关高血压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，导致神经体液机制的持续改变。研究计划通过测试以下假设，在概念上推进我们对血压中枢调节的理解：1。脑中一种新形式的细胞内活性肾素在细胞内生成血管紧张素II中起重要作用，并且是动脉压中枢调节的关键决定因素。2.在中枢神经系统的关键回路中氧化还原介导的NF κ B和AP-1的活化是Ang-II依赖性高血压发病机制中的致病分子事件。3.下丘脑中瘦素受体的不同信号通路调节对区域交感神经系统活动和动脉压的差异或选择性作用。4.中枢神经系统，特别是瘦素信号传导和/或神经元回路的缺陷在Bardet-Biedl综合征的高血压和肥胖中起主要的病理生理作用。该计划包括四个项目和三个核心，充分利用人类和小鼠遗传学，遗传操纵模型的开发和表征，分子生物学和细胞信号传导，位点选择性基因转移到大脑，神经解剖学和高血压神经生理学的广泛专业知识。该项目的调查人员一直保持着出色的工作效率，并有证据表明项目和核心领导人之间进行了广泛的合作。事实上，每个项目的初步数据都来自高血压专业研究中心（SCOR）资助的前5年期间的概念进步和合作。