Genetic and Signaling Mechanisms in the Central Regulation of Blood

总体摘要 中枢神经系统(CNS)在肥胖和高血压中起着重要作用，但对 神经回路控制调节血压、进食和能量消耗的生理通路 仍然是有限的。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。其中许多机制在血压和新陈代谢神经中都是相同的 控制电路，但根据生理终点在中枢和大脑中的位置不同地控制它们 细胞通路被占用。我们将研究前脑和大脑中运行的分子机制 下丘脑改变高血压对心血管和代谢应激源的反应， 肾素-血管紧张素系统活性的调节机制及其与动脉血压和血管紧张素系统的关系 代谢功能、转运调控机制和关键受体调控功能 心血管和代谢功能，以及区别控制静息代谢的细胞内信号 心率和动脉压。项目1将测试前脑瘦素受体和小胶质细胞 在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 N-甲基-D-天冬氨酸激活在高血压反应增敏中的作用 感受器。项目2将检验以下假设：肾素-a和肾素-b在心脏 穹隆下器(SFO)、室旁核(PVN)和弓状核(ARC)介导局部 血管紧张素-II(Ang)的产生和作用，以控制自主神经输出，从而控制心血管和代谢 而肾素-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 饮食压力源。项目3将测试假设，功能障碍的蛋白质复合体，BBSome，在 导致普通饮食引起的肥胖以及与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的运输的细胞过程来激活 动态平衡和血压，以及b)通过干扰ARC前阿片黑素皮质素的放电活动 神经元。项目4将测试Ang作用于ARC的AgRP神经元上的AT1受体的假设 激活G蛋白信号转导调节因子-2(RGS2)敏感的GαI第二信使级联，它控制 AgRP的产生，从而调节黑素皮质素信号，最终控制热源SNA和 静息新陈代谢。这些项目在概念和技术上都是协同的，并将共同 增进我们对心血管神经控制的基本分子和细胞的理解 以及在健康和疾病中的代谢功能。从我们整合的拟议计划中获得的见解可以为 治疗高血压和肥胖症的新治疗方法的途径。

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.