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Metabolic alterations after aneurysmal subarachnoid hemorrhage

Award Number: K23NS121628
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Metabolic alterations after aneurysmal subarachnoid hemorrhage - 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 α-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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $183,857 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/27/2024	NON-COMPETING CONTINUATION	$183,857
														Subtotal = $183,857

Issue Date FY: 2024 ( Subtotal = $185,477 )
2024	2024	UNIVERSITY OF HEALTH SCIENCE CENTER	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/22/2023	NON-COMPETING CONTINUATION	$185,477
														Subtotal = $185,477

Issue Date FY: 2023 ( Subtotal = $185,477 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/5/2022	NON-COMPETING CONTINUATION	$185,477
														Subtotal = $185,477

Issue Date FY: 2022 ( Subtotal = $185,477 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/17/2021	NEW	$185,477
														Subtotal = $185,477

Grand Total All Awards = $740,288

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Metabolic alterations after aneurysmal subarachnoid hemorrhage

Award Number: K23NS121628

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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