Monday, June 30, 2025 6/30/2025

Oxidative Lipidomics in Pediatric Traumatic Brain Injury

Award Number: R37NS061817
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2025

Group Awards By:

View Award Description

Oxidative Lipidomics in Pediatric Traumatic Brain Injury - Each year in the US, severe TBI in children results in ∼7400 deaths and 60 000 hospitalizations. Fifty percent of surviving children with severe TBI have poor neurological outcome at six months. Severe TBI in children is thus a critical problem in desperate need of impactful therapies. Free radicals and oxidative stress have been uniformly accepted as universal pathogenic mechanisms of TBI prompting therapeutic use of antioxidants. Invariably, clinical trials of non-specific free radical scavengers/antioxidants failed. This suggests that true sources and mechanisms of TBI redox disbalance remain undefined, and represent a potential therapeutic opportunity. During the previous funding period we showed that lipid peroxidation after TBI in immature brain occurs as a result of controlled enzymatic reactions. We discovered that peroxidation of mitochondrial phospholipid cardiolipin (CL) represents a required stage of neuronal apoptosis after TBI in postnatal day (PND) 17 rats. We identified cytochrome c as a catalyst of CL peroxidation and showed that a mitochondria- targeted inhibitor of CL peroxidation suppressed TBI-induced apoptosis and preserved cognitive function in PND17 rats. Our latest work identified highly selective oxidation of arachidonic acid (AA) containing phosphatidylethanolamines (PE) by 15 lipoxygenase (15LOX) to be causative to ferroptosis. We discovered that PE binding protein 1 (PEBP1) complexes with 15LOX and changes its substrate specificity from free AA to AA esterified into PE to generate hydroperoxy-AA-PE death signals. Normally hydroperoxy-AA-PE are eliminated by combined action of glutathione peroxidase 4 (GPX4)/glutathione (GSH). Immature brain has lower GSH levels and GPX activity vs adult brain thus could be more vulnerable to ferroptosis upon injury. Indeed our preliminary data show that TBI leads to marked increase in expression and activity of 15LOX, and accumulation of oxidized AA-PE in PND17 rat brain. Furthermore, preliminary data indicate that inhibition of AA-PE oxidation suppresses TBI-induced neuronal death and preserves cognitive function. Thus, we hypothesize that generation of oxidized AA-PE by 15LOX/PEBP1 complex leads to neuronal death and represents a new target for drug discovery leading to innovative therapies in pediatric TBI. We propose to test our hypothesis in three Specific Aims. Aim 1 will determine the degree, spatial and temporal pattern of 15LOX/PEBP1 complex formation and AA-PE oxidation after TBI. Aim 2 will investigate the mechanisms of AA-PE oxidation in TBI-induced neuronal death. Aim 3 will design and investigate the mechanism of action and neuroprotective potential of small-molecule regulators of 15LOX and 15LOX/PEBP1 activity in TBI. These studies will employ powerful lipidomics and oxidative lipidomics technology to provide important mechanistic information on the role of PE oxidation in neuronal ferroptosis after pediatric TBI. The ability to selectively modulate PE oxidation, a critical early event in the mechanism of ferroptosis, could lead to targeted therapies for TBI and ultimately improve outcome for children after brain injury.


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: 2024 ( Subtotal = $317,067 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	14	5/15/2024	NON-COMPETING CONTINUATION	$317,067
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	14	8/19/2024	NON-COMPETING CONTINUATION	-$317,067
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	14	8/21/2024	NON-COMPETING CONTINUATION	$317,067
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	13	8/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$336,147
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	5/14/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$234,102
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	13	8/19/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$336,147
2024	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	5/14/2024	NON-COMPETING CONTINUATION	-$234,102
														Subtotal = $317,067

Issue Date FY: 2023 ( Subtotal = $336,147 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	8/31/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$336,147
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	8/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $336,147

Issue Date FY: 2022 ( Subtotal = $396,458 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	6/17/2022	NON-COMPETING CONTINUATION	$396,458
														Subtotal = $396,458

Issue Date FY: 2021 ( Subtotal = $391,250 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	4/30/2021	COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Grand Total All Awards = $1,440,922

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Oxidative Lipidomics in Pediatric Traumatic Brain Injury

Award Number: R37NS061817

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer