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

 描述（由申请人提供）：Kara Hughan博士是儿科内分泌学家和儿科助理教授，正在将自己确立为转化研究的学术领导者，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并建立预防措施。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测试她的假设。她的多学科指导团队将是至关重要的，以获得机械数据奠定基础的儿科RO 1补助金，引导她的职业生涯走向独立，并实现她的职业目标：（1）提高她的理解和经验的设计，进行和分析的bench-to-bedside机械I-II期临床试验;（2）开发一个包含多个学科的翻译工具箱，以应用于她未来的心脏代谢研究的新途径;（3）将从K12和K23实验室到床边的I-II期机制试验中获得的信息和技能应用于心血管疾病和代谢综合征的儿科试验，并建立一个综合性的儿科心脏代谢和线粒体中心。她将补充她的研究与板凳研究基础，先进的统计和临床试验设计，赠款写作和研究培训的负责任的行为，广告参与教育活动和科学会议在她感兴趣的领域课程。 虽然硝酸盐和亚硝酸盐传统上被认为是O氧化的惰性和潜在毒性代谢物，但现在认识到两者都可以再循环为生物活性NO。亚硝酸盐的氧化还原反应也可以与不饱和脂肪酸（如共轭亚油酸）反应，产生硝基脂肪酸（NO2-FA）。研究表明，线粒体将亚硝酸盐还原为NO，部分抑制线粒体呼吸，减少线粒体ROS的产生，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通路通过NO和NO2-FA介导信号传导，以降低血压，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产物，NO或NO2-FAs，调节这些生理功能，以及什么共同的机制可以解释他们的假定的治疗效果。因此，对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高血压人群并评估治疗效果提供了强有力的理论基础。这些发现形成了该提案的总体假设，即膳食补充亚硝酸盐产生NO和NO2-FA，以降低血压，抑制血小板活化，改善肥胖人群的胰岛素敏感性，内皮和线粒体功能，并代表了硝酸盐-亚硝酸盐-NO和心脏代谢领域的潜在概念性进展。

 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.