Genetic and Signaling Mechanisms in the Central Regulation of Blood

血液中枢调节的遗传和信号机制

• 批准号: 9977790
• 负责人: Curt Daniel Sigmund
• 金额: $ 185.13万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977790
• 关键词: American; Angiotensin II; Animal Model; Basal metabolic rate; Biochemistry; Blood; Blood Pressure; Brain; Brain region; Cardiovascular system; Cell Nucleus; Cell physiology; Defect; Diet; Disease; Disinhibition; Energy Metabolism; Epidemic; Functional disorder; Funding; Genetic; Genetically Modified Animals; Goals; Health; High Fat Diet; Homeostasis; Hypertension; Hypothalamic dysfunction; Hypothalamic structure; Incidence; Intervention; Knowledge; Liquid substance; Location; Mediating; Metabolic; Metabolic Control; Metabolism; Molecular; N-Methyl-D-Aspartate Receptors; Nerve; Neuraxis; Neurons; Obesity; Output; Pathologic; Pathway interactions; Personal Satisfaction; Physiological; Physiological Processes; Physiology; Play; Pro-Opiomelanocortin; Procedures; Process; Production; Prosencephalon; RGS2 gene; Regulation; Renin; Renin-Angiotensin System; Rest; Role; Second Messenger Systems; Signal Transduction; Standardization; Stimulus; Structure of nucleus infundibularis hypothalami; Subfornical Organ; Testing; United States; blood pressure regulation; feeding; health economics; innovation; insight; leptin receptor; neural circuit; neural network; neuroregulation; novel; novel therapeutic intervention; paraventricular nucleus; pressure; programs; protein complex; receptor; response; stressor; trafficking

Overall Summary The central nervous system (CNS) plays a major role in obesity and hypertension but the knowledge of the neural circuits controlling physiological pathways regulating blood pressure, feeding, and energy expenditure remain limited. The long term goal and central theme of the third competitive renewal of this program is to identify mechanisms and neural circuitry regulating blood pressure and energy homeostasis in hypertension and common obesity. Many of these mechanisms are shared among blood pressure and metabolic neural control circuits but differentially control physiological endpoints by virtue of their location in the CNS and the cellular pathways engaged. We will examine molecular mechanisms operating in the forebrain and hypothalamus which alter the hypertensive response to cardiovascular and metabolic stressors, the mechanisms regulating renin-angiotensin system (RAS) activity and its relationship with arterial pressure and metabolic function, mechanisms regulating the trafficking and function of critical receptors regulating cardiovascular and metabolic functions, and the intracellular signals that differentially control resting metabolic rate and arterial pressure. Project 1 will test the hypothesis that forebrain leptin receptors and microglial activation in the neural network controlling sympathetic tone and body energy metabolism play a fundamental role in sensitization of the hypertensive response which is mediated by activation of N-Methyl-D-aspartate receptors. Project 2 will test the hypotheses that the coordinated expression of renin-a and renin-b in the subfornical organ (SFO), paraventricular nucleus (PVN), and arcuate nucleus (ARC) mediates local angiotensin-II (ANG) production and action to control autonomic output and thus cardiovascular and metabolic endpoints; and that disinhibition of renin-a expression with concomitant inhibition of renin-b expression in the SFO, PVN and ARC is required to mediate sensitization of the hypertensive response to mild humoral and dietary stressors. Project 3 will test the hypotheses that dysfunction a protein complex, the BBSome, in the contributes to common diet-induced obesity and to obesity-associated hypertension and sympathetic nerve activation by a) altering the cellular processes underling the trafficking of the receptors that regulate energy homeostasis and blood pressure, and b) by interfering with the firing activity of ARC proopiomelanocortin neurons. Project 4 will test the hypothesis that ANG acts at AT1 receptors on AgRP neurons of the ARC to activate a regulator of G-protein signaling-2 (RGS2)-sensitive Gαi second-messenger cascade, which controls AgRP production and thus modulates melanocortin signaling, ultimately to control thermogenic SNA and resting metabolism. These projects are synergistic both conceptually and technically and will collectively advance our understanding of the basic molecular and cellular that underlie neural control of cardiovascular and metabolic functions in health and disease. Insights gained from our integrated proposed program can pave the way for novel therapeutic approaches for the treatment of to hypertension and obesity.

总结 中枢神经系统（CNS）在肥胖和高血压中起着重要作用，但了解 控制血压，喂养和能量消耗的物理途径的神经回路 保持有限。该计划的第三个竞争续约的长期目标和中心主题是 确定高血压中血压和能量体内稳态的机制和神经回路 和普通肥胖。这些机制中的许多是在血压和代谢中性中共享的 控制电路，但由于CNS中的位置和 蜂窝路径参与。我们将检查在前脑中运行的分子机制，并 下丘脑会改变对心血管和代谢压力源的高血压反应， 调节肾素 - 血管紧张素系统（RAS）活性的机制及其与动脉压的关系 代谢功能，重新计算关键接收器的贩运和功能的机制 心血管和代谢功能以及不同控制静息代谢的细胞内信号 速率和动脉压。项目1将检验前脑瘦素受体和小胶质细胞的假设 控制同情语调和身体能量代谢的神经网络中的激活发挥了基本 在高血压反应的敏感性中的作用，这是通过N-甲基-D-天冬氨酸激活介导的 接收者。项目2将检验以下假设，即在 副构造器官（SFO），旁牙核（PVN）和弧形核（ARC）培养局部 血管紧张素-II（ANG）的生产和动作，以控制自主产量，因此心血管和代谢 端点；并抑制肾素A的表达，并抑制肾素-B表达 SFO，PVN和ARC是需要对轻度体液和轻度反应的培养基敏感性和 饮食压力。项目3将测试在蛋白质复合物中功能障碍的假设 有助于常见的饮食引起的肥胖症以及肥胖相关的高血压和交感神经 通过a）激活调节能量的接收器贩运的细胞过程 稳态和血压，b）通过干扰弧蛋白皮质的发射活性 神经元。项目4将检验以下假设：ANG在AT1受体上作用于AT1受体的AGRP神经元至 激活G蛋白信号-2（RGS2）的调节剂 - 敏感的GαI第二门级别级联 AGRP产生，因此调节黑色素质素信号传导，最终控制热sna和 休息代谢。这些项目在概念和技术上都是协同的，并且将集体 促进我们对心血管神经控制基础的基本分子和细胞的理解 以及健康和疾病的代谢功能。从我们综合提出的计划中获得的见解可以铺路 新颖的治疗方法治疗高血压和肥胖的方法。