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

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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.