Mentoring in cholinergic regulation of vascular oxidation

项目摘要/摘要 这份K24提案将为Cyndya Shibao博士提供高质量的指导时间，以 范德比尔特大学医学中心的博士后和初级教员研究员。在这方面，她 提出全面而专注的指导计划，以促进她的有效过渡 被辅导者进入独立的学术生涯。她的申请包括一项全面的战略，以 通过获得指导、多元化培训、领导力和 战略规划。此外，她的研究计划还包括与范斯坦学会成员的交叉合作 生物电子医学研究所将获得迷走神经刺激方面的额外专业知识，这是 主题链接到她目前对副交感胆碱能调节血管氧化的研究。 内皮功能障碍是一种促血栓形成的炎症状态，会导致血管反应性受损 动脉粥样硬化和心血管疾病(CVD)发展的早期可逆步骤。多重 研究一直表明，非裔美国人(AAs)与 白色的。非裔美国人的心血管发病率也高得不成比例，死亡率高出20%。 而不是白人或西班牙裔。血管内皮细胞功能障碍是由活性氧产生过多引起的 (ROS)，特别是干扰内皮源性一氧化氮信号通路的超氧化物歧化酶。其中之一 超氧化物的主要来源是NADPH氧化酶；我们以前的工作发现，NADPH氧化酶的激活 通过激活免疫细胞促进血管氧化。众所周知，炎症和 氧化应激由副交感神经系统(PNS)调节。石宝博士等人 研究发现，与白人相比，AAS降低了PNS的活性。目前，她资助的研究是 集中于中枢性胆碱酯酶抑制，增加胆碱能活性，对血管的影响 这一人群中的氧化应激。对于这项K24应用，她将扩大这些研究，以确定是否跨- 耳迷走神经刺激(TaVNS)是另一种刺激三叉神经痛的干预措施，可防止免疫细胞 激活，减少收获内皮细胞的血管氧化标记物，改善内皮 功能通过流动介导的扩张来测量。计划中的研究将提供一个全面的 三七总皂苷传递增加对血管氧化和细胞毒性的影响 炎症，这是非裔美国人血管内皮细胞功能障碍的先兆。此外，这些研究将 为世宝博士的学员提供充足的血管胆碱能调节方面的培训机会 氧化。

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.