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(CNS)在血压和体重的调节中起着重要作用，这些通路的异常可导致高血压和肥胖。肥胖和高血压仍然是世界范围内的一个严重的健康问题，特别是在高血压和肥胖相关高血压发病率持续上升的西方社会。血压和代谢中枢调节(CRBPM)PPG的长期目标和中心主题是了解中枢血管紧张素(Ang)和瘦素(Leptin)在高血压和肥胖相关高血压中调节血压的基本机制，以及它们在能量稳态上的趋同。该计划将侧重于高血压和饮食诱导肥胖(Dig)中中枢肾素-血管紧张素系统(RAS)的激活条件和瘦素信号的改变，以及脑内质网(ER)和氧化应激作为调节交感神经活动(SNA)、血压和能量平衡的机制的作用。这些项目将检验几个新的假设。项目1假设ER/氧化剂应激导致Dig小鼠肾脏SNA和血压的增加，但反过来作用于SFG-PVN轴，以钝化或逆转脑血管紧张素和/或瘦素介导的促进肥胖-高血压模型中热源性SNA和能量消耗的作用。项目2将检验这一假说，即大脑中局部合成Ang通过重叠但离散的Ang依赖机制和传出通路控制血压、水分摄入和能量消耗，而Dig通过AT2R依赖机制刺激脂肪RAS作用，从而钝化脑RAS激活对能量消耗的影响。项目3将测试一种假设，即中枢神经系统中的BBS基因对控制能量平衡和血压自主调节至关重要，脑BBS基因缺陷、受体运输、内质网应激和脑RAS与BBS相关的代谢、自主神经和血压变化密切相关。该计划的重点和凝聚力很强，并通过一个行政核心和两个科学核心得到加强。研究人员工作效率高、互动性强，将采用复杂的分子、遗传学和生理学方法。这些发现将阐明重要的机制，这些机制可能会转化为改善高血压和肥胖-高血压患者心血管和代谢功能障碍的治疗。

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.