This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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