Mitochondrial-targeted antioxidant supplementation for improving cerebrovascular function in postmenopausalwomen

PROJECT SUMMARY CANDIDATE: Kevin O. Murray, PhD, is a postdoctoral fellow training in vascular aging at the University of Colorado (CU) Boulder. In this K01 application, Dr. Murray aims to determine the efficacy of mitochondrial- targeted antioxidant (MitoQ) treatment for improving cerebrovascular function in estrogen-deficient postmenopausal (PME-) women. His immediate goal is to acquire the research training and professional skills necessary to transition to an independent, extramurally funded investigator. His long-term goal is to establish his own research program with a focus on identifying novel, evidence-based alternative interventions that improve vascular function and prevent or delay the development of age- and menopause-related comorbidities and chronic diseases. CAREER DEVELOPMENT PLAN: Dr. Murray’s career development plan consists of: 1) determining the efficacy of MitoQ vs placebo for improving cerebrovascular function in PME- women; 2) acquiring new skills to assess cerebrovascular function to support his proposed research plan; 3) professional skill development through coursework and attendance/presentations at weekly journal clubs, CU seminars, and national scientific meetings; and (4) regular interactions with his mentor team. ENVIRONMENT: The environment for Dr. Murray’s training plan will be exceptional. Dr. Murray’s primary mentor, Dr. Douglas Seals, and co-mentor, Dr. Kerrie Moreau, are internationally recognized, NIH-funded scientists with strong records of successful mentoring in translational biomedical research. Co-mentor Dr. Philip Ainslie is the Canada Research Chair in Cerebrovascular Physiology with extensive experience assessing cerebrovascular function. Consulting mentors: (1) Dr. Michel Chonchol has served as physician of record for the previous and ongoing MitoQ trials conducted by the primary mentor’s laboratory and will provide additional mentoring related to performing clinical research; (2) Dr. Zhying You is a Senior Biostatistician in the Department of Medicine at the CU Anschutz Medical Campus and provides mentoring to trainees and faculty conducting clinical trials; (3) Dr. Zachary Clayton is an expert in assessing vascular function in mice, particularly through the role of changes in the circulating milieu; and (4) Dr. Aurelie Ledreux is an expert in brain aging and the role of extracellular vesicles. RESEARCH: PME- women are at an increased risk of cardiovascular disease (CVD), including stroke, due, in part, to cerebrovascular dysfunction in response to excess mitochondrial reactive oxygen species and consequent reductions in nitric oxide bioavailability and increases in arterial stiffness. This clinical trial will determine whether an oral supplement called MitoQ, which reduces the production of damaging reactive oxygen species from mitochondria, can improve cerebrovascular function in PME- women, and will provide insight into the biological reasons (mechanisms) by which supplementation with MitoQ exerts these benefits. Overall, this research will provide scientific evidence supporting the use of MitoQ for improving cerebrovascular function and decreasing CVD risk, such as stroke, in PME- women.