CHOLINERGIC MODULATION OF CYTOKINE SYNTHESIS IN SEPSIS SURVIVORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 以前的文献已经证实炎症性疾病状态下存在潜在的自主神经系统功能障碍，特别是败血症。我们最近证实，在炎症动物模型中，通过副交感神经系统的迷走神经发出的胆碱能信号可以抑制炎症和细胞因子的释放。这种抑制依赖于尼古丁特异性受体α亚单位。我们现在将这种中枢神经系统控制炎症的机制称为“胆碱能抗炎途径”。测量人类志愿者迷走神经活动的一种方法是通过心率变异性。心率变异性测量受试者的静息心电图模式，量化每个R-R距离，通过数学计算，快速傅立叶变换将该信号转换为视觉上不同的频率。这两个不同的频率，称为低频和高频(低频和高频)，反映了受试者的交感迷走神经平衡。 我们的第一个目标是通过心率变异性来量化受试者的迷走神经张力，并将其与他们对特定尼古丁激动剂的体外细胞反应相关联。替代研究的终点是在刺激性全血试验中测量专有α激动剂(CAP 68)的胆碱能活性。然后，我们将全血中的胆碱能活性与受试者的心率变异性相关，心率变异性是迷走神经张力的一种衡量标准(具体而言，低频与高频比率(LF/HF))。我们还在测量阿尔法亚单位的表达，以确定这种受体是否在严重脓毒症患者的炎症中发挥作用，严重脓毒症是一种涉及持续炎症的疾病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previous literature has established the presence of underlying autonomic nervous system dysfunction in inflammatory disease states, in particular, sepsis. We recently established that cholinergic signaling through the vagus nerve of the parasympathetic nervous system inhibits inflammation and cytokine release in animal models of inflammation. This inhibition is dependent on the nicotinic-specific receptor alpha subunit. We now refer to this mechanism for CNS control of inflammation as the "cholinergic anti-inflammatory pathway." A method of measuring human volunteers' vagus nerve activity is through heart rate variability. Heart rate variability measures a subject's resting electrocardiogram pattern, quantifies each R-R distance and, through a mathematical calculation, fast fourier transform, converts this signal into visually distinct frequencies. These two distinct frequencies, termed low and high frequencies (LF and HF) reflect a subject's sympathovagal balance. Our first goal is to quantify a subject's vagus nerve tone through heart rate variability and correlating this to their cellular response ex vivo to specific nicotinic agonists. A surrogate study end point is to measure the cholinergic activity of a proprietary alpha agonist (CAP 68) on a stimulated whole blood assay. We are then correlating the cholinergic activity in the whole blood assay with the subjects' heart rate variability, a measure of vagus nerve tone (specifically, low frequency to high frequency ratios (LF/HF). We are also measuring alpha subunit expression to determine whether this receptor plays a role in inflammation in subjects with severe sepsis, a disease that involves ongoing inflammation.