PROJECT SUMMARY/ABSTRACT
The purpose of this F32 application is to support Dr. Kevin Murray, a promising first-year postdoctoral fellow
in the laboratory of Dr. Douglas Seals, to conduct original research and receive scientific training that will
prepare him to become an independent, extramurally funded investigator in the field of translational vascular
physiology aimed at identifying novel interventions for improving vascular function with aging and the
associated mechanisms of action. Dr. Murray will learn a variety of new technical, conceptual, and professional
skills, including focused training in translational cellular and molecular vascular physiology research, in addition
to training in conducting a clinical trial. His proposed research project will leverage his primary sponsor’s
ongoing NIH-funded R01-funded clinical trial that seeks to establish the efficacy of the mitochondria-targeted
antioxidant MitoQ for improving vascular endothelial function in older adults to determine (Aim 1) whether
changes in the circulating milieu following 3 months of chronic treatment with MitoQ improves endothelial cell
function by treating human aortic endothelial cells (HAECs) with plasma collected from subjects after MitoQ or
placebo treatment. He will also determine (Aim 2) if reductions in oxidized low-density lipoprotein (oxLDL)
following MitoQ treatment mediate improvements in endothelial cell function by ameliorating oxLDL-stimulated
mitochondrial fission. Lastly, he will also explore (Aim 3) the role of changes in extracellular vesicles (EVs) with
MitoQ treatment in mediating improvements in endothelial cell function and whether these potential changes
are associated with alterations to miRNA content of EVs. Age-related endothelial dysfunction is largely
mediated by reduced bioavailability of the vasoprotective molecule, nitric oxide (NO), as a result of excessive
production of reactive oxygen species (ROS). Dysfunctional mitochondria increase with age and are a major
source of excess ROS (mtROS) in the vasculature. MitoQ is a mitochondrial-targeted antioxidant and our
laboratory previously showed that 6-weeks of MitoQ supplementation in older adults improved NO-mediated
endothelium-dependent dilation. Preliminary data collected by Dr. Murray for this application suggest that
changes to the circulating milieu following MitoQ treatment increase NO bioavailability and decrease mtROS
bioactivity in HAECs ex vivo, extending the mechanisms of action by which MitoQ supplementation improves
endothelial function. Guided by these strong preliminary data, Dr. Murray will aim to establish changes to the
circulating milieu as a mechanism of action by which MitoQ treatment improves endothelial function by
leveraging plasma samples collected from subjects during his primary sponsor’s ongoing NIH-funded R01
clinical trial. The primary sponsor is an internationally recognized, NIH-funded scientist with a strong history of
successful mentoring in translational biomedical research. With his guidance, and that of his mentoring team,
Dr. Murray will be able to successfully complete the proposed research and training plan, preparing him to
succeed as an extramurally funded independent investigator in translational vascular physiology.
