PROJECT SUMMARY
Aneurysmal subarachnoid hemorrhage (aSAH) affects 50,000 people per year in the U.S., causing significant
morbidity and mortality. Patients with aSAH are at risk of developing secondary complications such as
vasospasm and delayed cerebral ischemia (DCI). Despite adequate surgical treatment of aneurysmal rupture
and aggressive medical management, few effective treatments exist to prevent DCI and late complications
after aSAH. Furthermore, patients with aSAH are susceptible to systemic complications involving numerous
organ systems including the heart, lungs, and kidneys and are known to have systemic elevations in
proinflammatory cytokines. The purpose of this research proposal is to define the metabolic changes that
occur after aSAH and their relationship to systemic inflammation. Marked metabolic changes occur after brain
injury with a shift from oxidative phosphorylation (OXPHOS) to glycolysis. This increased reliance on glycolytic
metabolism is required for the activation of immune effector cells. My preliminary results show decreased
levels of tricarboxylic acid (TCA) cycle metabolites and increased levels of glycolytic metabolites in the plasma
of aSAH patients. Lower levels of fumarate and a-ketoglutarate are associated with worse functional
outcomes. In Aim 1, we will use mass spectrometry to perform target metabolomics on retrospectively
collected plasma samples from patients with aSAH and controls. A metabolic signature after aSAH will be
defined, and bioinformatics methods will be used to investigate which metabolites drive proinflammatory
cytokine production. In Aim 2, peripheral blood monocyte oxidative metabolism will be quantified.
Metabolomics will be performed from prospectively collected monocytes. Peripheral blood monocyte
mitochondrial respiration will be quantified compared with controls and across disease severity. The
relationship between the monocyte intracellular proinflammatory cytokines and oxidative metabolism including
mitochondrial membrane potential will be investigated. The ability of metabolically targeted treatments
(metformin, dimethylfumarate, and glutamine) to bolster oxidative metabolism and decrease monocyte
proinflammatory cytokine production will be investigated. This project will include training for Dr. Gusdon to
further his development as a physician-scientist through a rigorous curriculum developed in the Center for
Clinical and Translational Sciences and School of Biomedical Informatics. This will include dedicated statistical
and bioinformatics training and focused mentorship with experts in translational and basic research. The
project will be performed at the McGovern Medical School at UTHealth- Memorial Hermann Hospital.