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

基本信息

批准号：
9278663
负责人：
Curt Daniel Sigmund
金额：
$ 5.36万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9278663
关键词：
Accreditation Address Adipose tissue Affect Angiotensin Receptor Angiotensins Animals Autonomic Dysfunction Biological Markers Blood Pressure Body Weight Brain Breeding Cardiovascular system Complement Consult DOCA Data Data Analyses Defect Diet Disease Dissociation Efferent Pathways Electron Microscopy Endoplasmic Reticulum Energy Metabolism Equipment Fatty acid glycerol esters Functional disorder Generations Genes Genetic Genotype Goals Harvest Health Homeostasis Human Hypertension Hypothalamic structure In Vitro Incidence Injection of therapeutic agent Institution Iowa Kidney Leptin Leptin resistance Link Maintenance Measurement Mediating Mediator of activation protein Metabolic Metabolism Methods Microscopic Modality Modeling Molecular Molecular Genetics Mus Nerve Neuraxis Neuroanatomy Neurons Obesity Oxidation-Reduction Oxidative Stress Pathway interactions Peripheral Phase Physiological Play Population Predisposition Preparation Pro-Opiomelanocortin Process Production Progress Reports Proteins Quality Control Recruitment Activity Regulation Renin-Angiotensin System Research Research Personnel Robin bird Role Services Signal Transduction Site Societies Structure of nucleus infundibularis hypothalami Subfornical Organ Technical Expertise Techniques Testing Training Transgenic Animals Transgenic Mice Transgenic Model Transgenic Organisms Translations Universities Viral Vector Water consumption Work blood pressure regulation cost effective design endoplasmic reticulum stress energy balance improved innovation instrumentation knockout animal leptin receptor light microscopy medical schools mind control model design mouse model neurophysiology neuroregulation novel oxidant stress paraventricular nucleus pressure programs receptor repository research study response symposium trafficking viral gene delivery

项目摘要

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.

描述（由申请人提供）：中枢神经系统（CNS）在调节血压和体重的调节中起着重要作用，这些途径中的异常会导致高血压和肥胖。肥胖和高血压仍然是全球严重的健康问题，尤其是在西方社会中，高血压和与肥胖相关的高血压的发生率不断上升。血压和代谢中心调节（CRBPM）PPG的长期目标和中心主题是了解基本机制，通过这些机制，中枢性血管紧张素（ANG）和瘦素在高血压和肥胖相关的高血压中调节血压，以及它们对能量稳态的影响。该计划将重点介绍中央肾素 - 血管紧张素系统（RAS）的激活条件，并改变了瘦素信号在高血压和饮食诱导的肥胖症（DIG）中的改变，以及脑内质网（ER）（ER）的作用，氧化剂应激作为调节交感神经活性（SNA）的机制（SNA），血压和能量稳态。这些项目将检验一些新的假设。项目1假设ER/氧化剂应激有助于挖掘小鼠的肾脏SNA和血压升高，但相反，在SFG-PVN轴上起作用，以钝化或反向脑Ang和/或瘦素介导的对热基因SNA的促进作用和能量对这种肥胖 - - 肥胖模型的促进作用。项目2将通过重叠但离散的ANG依赖机制和传出途径来检验ANG局部合成的假设，可以控制血压，水的摄入量和能量消耗，并通过通过AT2R依赖性机制刺激ADIPOSE RAS来刺激脑RAS激活对能量消耗的影响。项目3将检验以下假设：中枢神经系统中的BBS基因对于控制能量稳态和血压的自主神经调节至关重要，而脑BBSOME，受体运输，ER压力和脑部RAS的缺陷与与BBS相关的代谢，自主和血压反应至关重要。该计划紧密集中和凝聚力，并通过一个行政和两个科学核心加强。研究人员的生产力高，互动性，并将采用复杂的分子，遗传和生理方法。这些发现将阐明重要的机制，这可以使改进的高血压和肥胖 - - 高血压中心血管和代谢功能障碍的治疗方法改进。