Mentoring in cholinergic regulation of vascular oxidation

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PROJECT SUMMARY/ABSTRACT This K24 proposal will provide protected time for Dr. Cyndya Shibao to deliver high-quality mentoring to post-doctoral and junior faculty investigators at Vanderbilt University Medical Center. In this regard, she proposes a comprehensive and dedicated mentoring plan that will facilitate the effective transition of her mentees into independent academic careers. Her application includes an across-the-board strategy to augment her training through acquisition of advanced skills in mentoring, training in diversity, leadership, and strategic planning. In addition, her research plan includes a cross-collaboration with members of the Feinstein Institute of Bioelectronic Medicine to acquire additional expertise in vagus nerve stimulation, which is thematically link to her current studies on parasympathetic cholinergic regulation of vascular oxidation. Endothelial dysfunction, a pro-thrombotic, inflammatory condition that causes impaired vascular reactivity is an early reversible step in the development of atherosclerosis and cardiovascular disease (CVD). Multiple studies consistently shown that African Americans (AAs) have impaired endothelial function compared to whites. African Americans also experience disproportionately higher CV morbidity and 20% higher mortality than whites or Hispanics. Endothelial dysfunction is caused by the overproduction of reactive oxygen species (ROS), particularly superoxide which interferes with endothelial-derived nitric oxide signaling pathways. One of the major sources of superoxide is NADPH oxidase; our previous work found that activation of NADPH oxidase contributes to vascular oxidation through immune cell activation. It is well-known that inflammation and oxidative stress are modulated by the parasympathetic nervous system (PNS). Dr. Shibao and others found that AAs have reduced PNS activity compared with whites. Currently, her funded studies are focused on the effect of central acetylcholinesterase inhibition, which increases cholinergic activity, on vascular oxidative stress in this population. For this K24 application, she will expand these studies to determine if trans- auricular vagus nerve stimulation (TaVNS), another intervention that stimulates PNS, prevents immune cell activation, reduces markers of vascular oxidation in harvested endothelial cells and improve endothelial function as measured by flow-mediated dilation. The planned studies will provide a comprehensive assessment of the mechanism underlying the effect of increased PNS transmission on vascular oxidation and inflammation, which precedes endothelial dysfunction in African Americnas. Furthermore, these studies will provide ample training opportunities for Dr. Shibao’s mentees in the area of cholinergic regulation of vascular oxidation.