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

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DESCRIPTION (Provided by applicant): The central nervous system (CNS) plays important roles in the regulation of blood pressure and body weight, and abnormalities in these pathways can cause both hypertension and obesity. Obesity and hypertension remain a serious health problem worldwide, in particular in Western societies where the incidence of hypertension and obesity-associated hypertension continues to rise. The long term goal and central theme of the Central Regulation of Blood Pressure and Metabolism (CRBPM) PPG is to understand fundamental mechanisms by which central angiotensin (ANG) and leptin regulate blood pressure in hypertension and obesity-associated hypertension, and their convergence on energy homeostasis. The Program will focus on conditions of activation of the central renin-angiotensin system (RAS) and altered leptin signaling in hypertension and diet-induced obesity (DIG), and on the role of brain endoplasmic reticulum (ER) and oxidant stress as mechanisms regulating sympathetic nerve activity (SNA), blood pressure and energy homeostasis. The projects will test several novel hypothesis. Project 1 hypothesizes that ER/oxidant stress contributes to the increased renal SNA and blood pressure in DIG mice, but conversely acts in the SFG-PVN axis to blunt or reverse brain ANG- and/or leptin-mediated facilitatory effects on thermogenic SNA and energy expenditure in this model of obesity-hypertension. Project 2 will test the hypothesis of that local synthesis of ANG in the brain controls blood pressure, water intake, and energy expenditure through overlapping yet discrete ANG-dependent mechanisms and efferent pathways, and that DIG blunts the effects of brain RAS activation on energy expenditure by stimulating the adipose RAS acting through an AT2R-dependent mechanism. Project 3 will test the hypothesis that Bbs genes in the central nervous system are critical for the control of energy homeostasis and the autonomic regulation of blood pressure, and that defects in the brain BBSome, receptor trafficking, ER stress, and the brain RAS are critically involved in the metabolic, autonomic and blood pressure alterations associated with BBS. The Program is tightly focused and cohesive and is strengthen by one administrative and two scientific cores. The investigators are highly productive, interactive, and will employ sophisticated molecular, genetic, and physiological approaches. The findings will clarify important mechanisms, which may allow translation into improved treatment for cardiovascular and metabolic dysfunction in hypertension and obesity-hypertension.