Genetic and Signaling Mechanisms in the Central Regulation of Blood

总体汇总 中枢神经系统（CNS）在肥胖和高血压中起主要作用，但对中枢神经系统的认识还不够。 控制调节血压、进食和能量消耗的生理通路的神经回路 仍然有限。该计划第三次竞争性更新的长期目标和中心主题是 高血压患者血压和能量平衡调节机制及神经回路的研究 和普通肥胖症。这些机制中的许多在血压和代谢神经系统之间是共享的。 控制电路，但凭借其在CNS和CNS中的位置差异地控制生理端点。 细胞通路被激活我们将研究在前脑中运作的分子机制， 下丘脑改变高血压对心血管和代谢应激的反应， 调节肾素-血管紧张素系统（RAS）活性的机制及其与动脉压和 代谢功能，调节运输的机制和调节关键受体的功能 心血管和代谢功能，以及差异控制静息代谢的细胞内信号 心率和动脉压。项目1将检验前脑瘦素受体和小胶质细胞 控制交感神经张力和身体能量代谢的神经网络中的激活起着基础作用， 在由N-甲基-D-天冬氨酸激活介导的高血压反应增敏中的作用 受体。项目2将检验以下假设： 穹窿下器（SFO）、室旁核（PVN）和弓状核（ARC）介导局部 血管紧张素II（ANG）的产生和控制自主输出的作用，从而控制心血管和代谢 终点;并且在肾组织中，肾素-a表达的解除抑制伴随着肾素-b表达的抑制， SFO、PVN和ARC是介导高血压对轻度体液和体液免疫刺激的敏感性所必需的。 饮食压力源项目3将测试的假设，功能障碍的蛋白质复合物，BBSome，在 导致常见的饮食引起的肥胖和肥胖相关的高血压和交感神经 通过a）改变调节能量的受体运输的细胞过程来激活 稳态和血压，和B）通过干扰ARC前阿黑皮素的放电活性 神经元项目4将检验ANG作用于ARC的AgRP神经元上的AT 1受体的假设， 激活G蛋白信号传导-2（RGS 2）敏感性Gαi第二信使级联的调节因子， AgRP的产生，从而调节黑皮质素信号传导，最终控制产热SNA， 静息代谢这些项目在概念上和技术上都是协同的， 推进我们对心血管神经控制基础的基本分子和细胞的理解 和代谢功能的影响。从我们的综合建议计划中获得的见解可以铺平道路 为高血压和肥胖症的治疗开辟了新的途径。

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.