CHOLINERGIC MODULATION OF CYTOKINE SYNTHESIS IN SEPSIS SURVIVORS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。先前的文献已经确定了炎症性疾病状态，特别是脓毒症中存在潜在的自主神经系统功能障碍。我们最近确定，通过副交感神经系统的迷走神经胆碱能信号抑制炎症和细胞因子释放的动物模型中的炎症。这种抑制作用依赖于烟碱特异性受体α 7亚基。我们现在把这种中枢神经系统控制炎症的机制称为“胆碱能抗炎通路”。“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，并通过数学计算，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（LF和HF）反映了受试者的交感迷走神经平衡。 该项目的目标是双重的，并保持不变。目前，我们正在实现我们的第一个目标，即通过心率变异性量化受试者的迷走神经张力，并将其与他们对特定烟碱激动剂的离体细胞反应相关联。我们的第二个目标是确定通过生物反馈操纵受试者的迷走神经张力是否会改善严重脓毒症患者的长期生存。替代研究终点是在刺激全血测定中测量专有α 7激动剂（CAP 68）的胆碱能活性。然后，我们将全血测定中的胆碱能活性与受试者的心率变异性相关联，心率变异性是迷走神经张力的量度（具体地，低频与高频比（LF/HF））。我们还测量了α 7亚基的表达，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 7 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. The goals of this project are twofold and have remained the same. Currently, we are accomplishing our first goal that is to quantify subject's vagus nerve tone through heart rate variability and correlating this to their cellular response ex vivo to specific nicotinic agonists. Our second goal is to determine whether manipulating subjects' vagus nerve tone through biofeedback will improve the long term survival of patients who suffered an episode of severe sepsis. A surrogate study end point is to measure the cholinergic activity of a proprietary alpha 7 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 7 subunit expression to determine whether this receptor plays a role in inflammation in subjects with severe sepsis, a disease that involves ongoing inflammation.