Regulation of pulmonary vascular cell redox state by L-2-hydroxyglutarate

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 DESCRIPTION (provided by applicant): The NIH Mentored Clinical Scientist Research Career Development Award (K08) proposal describes a five- year training program for career development in academic pulmonary medicine. The principal investigator, William Oldham, M.D., Ph.D., is an Associate Physician and Instructor of Medicine in the Division of Pulmonary and Critical Care Medicine at the Brigham and Women's Hospital (BWH) and Harvard Medical School. He has a background in chemistry and biochemistry and completed doctoral research in pharmacology while a member of the NIH Medical Scientist Training Program at Vanderbilt University. He completed clinical training in Internal Medicine, Pulmonary Disease, and Critical Care Medicine in 2012. His goal is to develop a successful career as an independently funded physician-scientist investigating redox metabolism in pulmonary vascular disease. With the support and protected time provided by the K08 award, Dr. Oldham will develop expertise in the fields of energy metabolism, redox biochemistry, mitochondrial physiology, and dynamic modeling from formal coursework, independent study, and practical experience with relevant experimental techniques. Dr. Joseph Loscalzo, an internationally recognized expert in these areas with over 30 years of mentoring experience, will mentor Dr. Oldham with the support of an advisory committee composed of outstanding scientists in metabolism and pulmonary disease. As the award period progresses, Dr. Oldham will develop the skills necessary for a successful R01 grant submission. Dr. Oldham will work in the Division of Pulmonary and Critical Care Medicine in the Department of Medicine at BWH, an outstanding scientific and mentoring environment located within the heart of the Harvard Medical School community. Pulmonary arterial hypertension affects 15-50 people per million and elevated pulmonary artery pressures con- tribute to increased morbidity and mortality of millions more affected by lung disease, heart failure, and other conditions. Metabolic abnormalities in PAH offer a rich potential for the development of much-needed disease modifying therapies for this condition. Dr. Oldham's long-term goal is to define the metabolic derangements underlying PAH and to develop therapies targeting the resulting metabolic vulnerabilities. The overall objective of this application is to define the role of L2HG in the pathogenesis of PAH as the first step toward his long- term goal. The central hypothesis is that L2HG production supports pulmonary vascular remodeling in PAH by increasing pro-proliferative reactive oxygen species generation in pulmonary vascular cells. The rationale for this proposal is that, once the links between L2HG metabolism and PAH pathogenesis are defined, these bio- chemical pathways can be targeted pharmacologically, resulting in novel and disease-modifying therapies for PAH. The central hypothesis will be tested by pursuing the following specific aims: (1) Determine the biochemical link between L2HG metabolism, glycolysis, and cellular redox state using biochemical and kinetic modeling approaches; (2) Determine the impact of L2HG metabolism on pulmonary vascular cell phenotype using genetic manipulations of L2HG levels and readouts of cell proliferation, apoptosis, and reactive oxygen species production; and (3) Determine the role of L2HG metabolism in the development of PAH using genetically modified mice. The contribution of this work is expected to be a mechanistic understanding of how L2HG metabolism regulates cellular redox homeostasis in support of pulmonary vascular remodeling in PAH. This contribution will be significant because it will define a critical role for L2HG in normal and diseased metabolism that will enhance our understanding of the cellular response to hypoxia and other stressors. The proposed research is innovative because it represents a new and substantive departure from the status quo by defining an important role for L2HG metabolism in cellular redox homeostasis. This research will open new horizons in the study of intracellular redox signaling. Moreover, this pathway has not been previously associated with PAH and represents a new area for mechanistic investigations of disease pathogenesis. Since L2HG is not an intermediate in any known metabolic pathway, its metabolism may offer safe and tractable experimental and therapeutic tar- gets for manipulating cellular redox state, which would provide a valuable tool for future investigations of this deadly disease.