PROJECT SUMMARY/ABSTRACT The objectives of this K08 proposal are to foster the development of critical scientific and professional skills that will allow the candidate, Dr. Mona Alotaibi, to advance toward her goal of becoming an independent investigator; and to investigate the role of metabolic dysregulations and bioactive molecular markers of endothelial dysfunction in modulating pulmonary arterial hypertension (PAH) progression in human studies and experimental models. This will be achieved through a comprehensive training plan and extensive laboratory experience and course work, which will provide Dr. Alotaibi additional expertise in experimental design, laboratory procedures, large data handling and laboratory leadership skills. Pulmonary arterial hypertension is a rare but life-threatening condition, that if left untreated leads to right ventricular failure and death. Despite advances in therapeutics, PAH mortality and morbidity remains unacceptably high, motivating efforts to identify circulating biomarkers and mechanistic targets that could improve tailored treatment approaches and outcomes. Central to PAH pathobiology is endothelial dysfunction governed by imbalance between endothelial derived relaxing and contracting factors. These factors include circulating small bioactive lipid mediators, eicosanoids known to exhibit vasoactive properties including vasocontraction or vasodilation in context dependent matter. Sensitive methods for comprehensively detecting and quantifying distinct eicosanoid species have been limited with prior studies in PAH focusing mainly on cyclooxygenase pathway. We have shown that distinct lipoxygenase (LOX)-eicosanoid dysregulations exist in animal models with severe pulmonary hypertension and these metabolites associated with mortality and worse clinical outcomes in human. The overall goal of this proposal is to utilize our newly developed mass spectrometry approaches together with comprehensive, complementary study design that i