ROS Signaling in Baroreeeptor and Sympathetic Neurons in Normal and Heart Failure

压力感受器传入神经元（BRN）的膜特性和相关电兴奋性， 传出交感神经元（SN）是压力反射敏感性和交感神经元的重要决定因素。 驱动最近的研究表明，BRN和SN都可以产生活性氧（ROS），但 关于ROS在这些神经元中的功能作用知之甚少。我们的初步数据表明， 降低BRN的兴奋性，但增加SN的兴奋性，这两种效应都促进交感神经元的增加。 神经活动和血压我们建议检验以下假设： 持续神经元激活（分钟）期间BRN和SN中产生的ROS作为信号传导 在生理条件下调节压力感受器和交感神经元活动的分子。 高胆固醇血症和高血压联合的新型小鼠模型中的慢性氧化应激 有助于自主神经/压力反射失调，以及随后的心脏自发发育 失败和灾难性事件。 BRN和SN是氧化应激的关键部位，也是ROS介导的功能障碍的靶点。 心衰 将使用各种实验方法，包括评估离子通道功能， 分离的BRN和SN中的兴奋性，siRNA和选择性肽抑制剂的病毒介导的基因转移 信号分子（例如，CaMKII、PKC）对神经节和神经元的作用，小鼠中的综合研究，以及全身 抗氧化剂疗法这些研究将定义产生ROS的有效刺激（例如，神经元 激活，血管紧张素II），和细胞内信号转导途径和离子通道的目标，参与 介导ROS依赖的兴奋性变化。患有高胆固醇血症、高血压和 最终的心力衰竭将通过使高胆固醇血症的载脂蛋白E+小鼠杂交产生， 高血压人肾素-血管紧张素原双转基因小鼠。因果关系 氧化应激、自主神经失调和进展为心力衰竭将被阐明， 在特定的时间窗口内实施抗氧化治疗，以防止或逆转功能性 赤字这些结果将促进我们对交感神经活动调节机制的理解， 为优化抗氧化剂治疗心脏自主神经失调提供见解 失败这项工作的重要性因下列因素造成的巨大公共卫生负担而得到强调： 心血管疾病和对心力衰竭患者更有效治疗的需求。

The membrane properties and associated electrical excitability of afferent baroreceptor neurons (BRN) and efferent sympathetic neurons (SN) are important determinants of baroreflex sensitivity and sympathetic drive. Recent studies have shown that both BRN and SN can produce reactive oxygen species (ROS), but little is known regarding the functional role of ROS in these neurons. Our preliminary data suggest that ROS decrease excitability of BRN but increase excitability of SN, both effects promoting increases in sympathetic nerve activity and blood pressure. We propose to test the following hypotheses: ¿ ROS produced in BRN and SN during sustained neuronal activation (minutes) function as signaling molecules that modulate baroreceptor and sympathetic neuronal activity under physiological conditions. ¿ Chronic oxidative stress in a novel mouse model of combined hypercholesterolemia and hypertension contributes to autonomic/baroreflex dysregulation, and subsequent spontaneous development of heart failure and catastrophic events. ¿ BRN and SN are key sites of oxidative stress and targets of ROS-mediated dysfunction in this model of heart failure. A variety of experimental approaches will be used including assessment of ion channel function and excitability in isolated BRN and SN, viral-mediated gene transfer of siRNAs and selective peptide inhibitors of signaling molecules (e.g., CaMKII, PKC) to ganglia and neurons, integrative studies in mice, and systemic antioxidant therapies. The studies will define effective stimuli for generation of ROS (e.g., neuronal activation, angiotensin II), and the intracellular signaling pathways and ion channel targets involved in mediating ROS-dependent changes in excitability. Mice with hypercholesterolemia, hypertension, and eventual heart failure will be generated by inter-breeding hypercholesterolemic apolipoprotein E~'~ mice and hypertensive human renin-angiotensinogen double transgenic mice. Cause-and-effect relationships between oxidative stress, autonomic dysregulation, and progression to heart failure will be illuminated by implementing antioxidant therapies within specific time windows designed to prevent or reverse functional deficits. The results will advance our understanding of mechanisms regulating sympathetic activity and provide insights into optimizing antioxidant therapies for treatment of the autonomic dysregulation of heart failure. The importance of the work is underscored by the enormous public health burden presented by cardiovascular disease and the need for more effective therapies for patients with heart failure.