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.
Using newly developed labeled oral nitrite, this project aims to further characterize the important mammalian nitrate-nitrite-nitric oxide (NO) pathway, to permit specific metabolite tracking of the signaling effectors in vivo, and to assess their therapeutic effects in two highly prevalent cardiovascular conditions, hypertension and the metabolic syndrome. While the candidate has the institutional resources and the multidisciplinary mentoring team available to her, the K23 grant award will provide the necessary protected time to enhance her career development training, to develop her translational toolbox into expertise, and the critical funding to translate her research findings from bench to bedside in the NO biology and cardiometabolic fields.
| Lai, Yen-Chun; Tabima, Diana M; Dube, John J et al. (2016) SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. Circulation 133:717-31 |
