Mentoring in cholinergic regulation of vascular oxidation

血管氧化的胆碱能调节的指导

• 批准号: 10664768
• 负责人: Cyndya Adriana Shibao
• 金额: $ 11.6万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664768
• 关键词: 3-nitrotyrosine; Academia; Academic Medical Centers; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Acute; African; African American population; Animal Model; Antigen-Presenting Cells; Aorta; Area; Atherosclerosis; Award; Blinded; Blood Vessels; Cardiovascular Diseases; Cause of Death; Chronic; Clinical Pharmacology; Collaborations; Credentialing; Dedications; Development; Ear lobe; Endothelial Cells; Endothelium; Enrollment; Event; Faculty; Foundations; Functional disorder; Funding; Galantamine; Harvest; Hispanic Populations; Hypertension; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Infusion procedures; Intercellular adhesion molecule 1; Intervention; Leadership; Link; Lipids; Measures; Mediating; Medicine; Mentors; Morbidity - disease rate; NADP; NADPH Oxidase; Nitric Oxide; Nitric Oxide Signaling Pathway; Outcome; Oxidative Stress; Parasympathetic Nervous System; Parents; Participant; Peripheral Blood Mononuclear Cell; Population; Postdoctoral Fellow; Production; Proteins; Publications; Reactive Oxygen Species; Regulation; Research; Research Personnel; Research Project Grants; Research Training; Signal Pathway; Source; Strategic Planning; Superoxides; Testing; Time; Tragus; Training; Work; adduct; bioelectronics; career; cholinergic; cytokine; effective therapy; endothelial dysfunction; experience; immune activation; immunogenic; improved; inflammatory marker; member; mid-career faculty; monocyte; mortality; neuroregulation; novel; novel strategies; oxidation; patient oriented; prevent; randomized placebo controlled study; response; skills; training opportunity; transmission process; vagus nerve stimulation; vascular endothelial dysfunction; vascular inflammation

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.

项目摘要/摘要 本K24提案将为Cyndya Shibao博士提供受保护的时间，以提供高质量的指导， 范德比尔特大学医学中心的博士后和初级研究人员。对此她 提出一个全面和专门的指导计划，以促进她的有效过渡， 学生进入独立的学术生涯。她的申请包括一个全面的战略， 通过获得指导方面的高级技能，多样性培训，领导力和 战略规划。此外，她的研究计划还包括与范斯坦委员会成员的交叉合作 生物电子医学研究所获得迷走神经刺激的额外专业知识， 主题与她目前对血管氧化的副交感胆碱能调节的研究有关。 内皮功能障碍是一种导致血管反应性受损的促血栓形成的炎症性疾病， 动脉粥样硬化和心血管疾病（CVD）发展的早期可逆步骤。多 研究一致表明，与非裔美国人（AA）相比， 白人非裔美国人的CV发病率也不成比例地高，死亡率高出20 比白人和西班牙裔人都多内皮功能障碍是由活性氧的过度产生引起的 (ROS)特别是干扰内皮源性一氧化氮信号通路的超氧化物。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 通过免疫细胞激活促进血管氧化。众所周知， 氧化应激受副交感神经系统（PNS）调节。石宝博士等人 研究发现，与白人相比，AA降低了PNS活性。目前，她资助的研究是 集中在中枢乙酰胆碱酯酶抑制，增加胆碱能活性，对血管的影响， 氧化应激反应对于这个K24应用程序，她将扩大这些研究，以确定是否跨- 耳迷走神经刺激（TaVNS），另一种刺激PNS的干预， 活化，减少收获的内皮细胞中的血管氧化标志物，并改善内皮细胞的功能。 通过流动介导的扩张测量功能。计划中的研究将提供全面的 评估PNS传输增加对血管氧化作用的潜在机制， 炎症，在非洲裔美国人中是内皮功能障碍的先兆。此外，这些研究将 为Shibao博士的学员在血管胆碱能调节领域提供充足的培训机会， 氧化