Nitrite Modulation of Hypertension, Platelet Activation and Endothelial and Mitochondrial Function

 描述(申请人提供)：Kara Hughan博士，儿科内分泌学家和儿科学助理教授，在翻译研究方面确立了自己的学术领袖地位，以了解与代谢综合征和线粒体功能障碍相关的心血管疾病的机制和预防措施。她的建议侧重于高血压和代谢综合征中的一氧化氮(NO)和线粒体生物学，并整合了最先进的翻译工具来验证她的假说。她的多学科指导团队将是获得机械数据的关键，为儿科RO1拨款奠定基础，指导她的职业生涯走向独立，并实现她的职业目标：(1)提高她在设计、实施和分析床边机械I-II期临床试验方面的理解和经验；(2)开发一个包含多个学科的翻译工具箱，以应用于她未来心脏代谢研究的新途径；(3)将从她的K12和K23床边机械性I-II期试验中获得的信息和技能集应用于心血管疾病和代谢综合征的儿科试验，并建立一个一体化的儿科心脏代谢和线粒体中心。她将通过以下课程来补充她的研究：板凳研究基础、高级统计学和临床试验设计、拨款撰写和负责任的研究培训、参加她感兴趣领域的教育活动和科学会议。虽然硝酸盐和亚硝酸盐传统上被认为是氧氧化的惰性和潜在的有毒代谢物，但现在人们意识到，两者都可以回收利用，生成生物活性的NO。亚硝酸盐的氧化还原反应也可以与不饱和脂肪酸反应，如共轭亚油酸，生成亚硝基脂肪酸(NO2-FA)。研究表明，线粒体将亚硝酸盐还原为NO，从而部分抑制线粒体呼吸，抑制线粒体ROS的生成，提示线粒体功能障碍和ROS的形成在高血压和代谢综合征的发病机制中起重要作用。研究表明，人的硝酸盐-亚硝酸盐-NO途径通过NO和NO2-FA介导信号转导，从而降低血压、抑制血小板活化、改善胰岛素敏感性、内皮和线粒体功能。然而，目前还不清楚亚硝酸盐代谢的哪些产物，NO或NO2-FAs调节这些生理功能，以及什么共同机制可以解释它们假定的治疗益处。因此，这一重要途径的进一步表征为使用口服亚硝酸盐治疗目标肥胖型高血压人群和评估治疗效果提供了强有力的理由。这些发现形成了该提案的总体假设，即饮食补充亚硝酸盐会产生NO和NO2-FA，以降低血压，抑制血小板激活，并改善肥胖人类的胰岛素敏感性、内皮和线粒体功能，并代表着硝酸盐-亚硝酸盐-NO和心脏代谢领域的潜在概念进步。

 DESCRIPTION (provided by applicant): Dr. Kara Hughan, a Pediatric Endocrinologist and Assistant Professor of Pediatrics, is establishing herself as an academic leader in translational research to understand the mechanisms and establish preventions of cardiovascular disease associated with metabolic syndrome and mitochondrial dysfunction. Her proposal focuses on nitric oxide (NO) and mitochondrial biology in hypertension and metabolic syndrome and integrates state-of-the-art translational tools to test her hypotheses. Her multidisciplinary mentoring team will be critical to obtain the mechanistic data to lay the foundation for a pediatri RO1 grant, to guide her career towards independence, and to achieve her career objectives: (1) to advance her understanding and experience in the design, conduct and analysis of bench-to-bedside mechanistic phase I-II clinical trials; (2) to develop a translational toolbox encompassing multiple disciplines to apply to new avenues of cardiometabolic investigations in her future; (3) to apply the information and skill sets obtained from her K12 and K23 bench-to-bedside mechanistic phase I-II trials to pediatric trials in cardiovascular disease and metabolic syndrome, and to develop an integrative pediatric cardiometabolic and mitochondrial center. She will complement her research with courses in bench research fundamentals, advanced statistics and clinical trial design, grant writing and responsible conduct of research training, ad participation in educational activities and scientific meetings in her areas of interest. While nitrate and nitrite were traditionally considered to be inert and potentially toxic metabolites of O oxidation, it is now appreciated that both can be recycled to bioactive NO. Redox reactions of nitrite can also react with unsaturated fatty acids, such as conjugated linoleic acid, to yield nito-fatty acids (NO2-FA). Studies have shown that mitochondria reduce nitrite to NO which partially inhibits mitochondrial respiration and attenuates mitochondrial ROS generation, suggesting mitochondrial dysfunction and ROS formation play an important role in hypertension and metabolic syndrome pathogenesis. Studies have suggested that the human nitrate-nitrite-NO pathway mediates signaling through NO and NO2-FA to reduce blood pressure, inhibit platelet activation and improve insulin sensitivity, endothelial and mitochondrial function. However, it remains unclear which products of nitrite metabolism, NO or NO2-FAs, modulate these physiological functions, and what common mechanism could account for their putative therapeutic benefits. Thus, further characterization of this important pathway provides a strong rationale to use oral nitrite to treat a targeted obese hypertensive population and assess the therapeutic effects. These findings form the proposal's overarching hypothesis that dietary supplementation with nitrite generates NO and NO2-FA to reduce blood pressure, inhibit platelet activation, and improve insulin sensitivity, endothelial and mitochondrial function in obese humans and represent a potential conceptual advance for the nitrate-nitrite-NO and cardiometabolic fields.