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The Role of Slc25a1 in Acute Pro-inflammatory Activation of Microglia/Macrophages Post-Traumatic Brain Injury

Award Number: R01NS150283
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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The Role of Slc25a1 in Acute Pro-inflammatory Activation of Microglia/Macrophages Post-Traumatic Brain Injury - Project Summary Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with an urgent need for therapies to mitigate long-term neurological deficits. Microglia and brain-infiltrating macrophages (Mi/MΦ) play a crucial role in post-TBI inflammatory responses, leading to progressive tissue damage and neurological impairments. Our research, along with other studies, suggests that dysregulated cellular metabolism contributes to the pro- inflammatory activation of Mi/MΦ, highlighting the potential for targeting specific metabolic modulators as a novel therapeutic strategy for TBI. Citrate production and conversion connect mitochondrial and cytosolic metabolism, with the mitochondrial citrate transporter Slc25a1 playing a key role in regulating mitochondrial bioenergetics, cytosolic fatty acid synthesis, and epigenetic modifications. Inhibition of Slc25a1 has shown promising results in shifting immune responses from pro-inflammatory to anti-inflammatory phenotypes. Our pilot study discovered increased Slc25a1 activation and citrate export from mitochondria to cytosol in microglia during the acute phase post-TBI, leading to mitochondrial bioenergetics dysfunction and increased acetylation of histone and NFκB. Slc25a1 deficiency or inhibition restored mitochondrial bioenergetics and reduced cytosolic citrate metabolism, attenuating pro-inflammatory activation, neurodegeneration, and neurological deficits. We hypothesize that acute Slc25a1 activation post-TBI increases mitochondria-to-cytosol citrate flux, reducing mitochondrial bioenergetics and increasing cytosolic citrate metabolism, which promotes pro-inflammatory Mi/MΦ activation and secondary brain damage. To test this, we propose three specific aims: (1) investigate the role of Slc25a1 activation in regulating mitochondria-to-cytosol citrate flux and mitochondrial bioenergetics/cytosolic citrate metabolism in Mi/MΦ at the acute phase after TBI in mice; (2) investigate the role of Slc25a1 activation in regulating Mi/MΦ pro-inflammatory phenotype and brain damage at the acute phase after TBI in mice; and (3) evaluate the impact of pharmacological inhibition of Slc25a1 activation on secondary brain damage and neurological outcomes after TBI in mice. Using genetic and pharmacological approaches, we aim to establish Slc25a1 as a crucial metabolic master switch in modulating Mi/MΦ activation and secondary brain injury following TBI. This study may ultimately inform the development of a novel and effective therapy for TBI.


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: 2026 ( Subtotal = $474,321 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/14/2026	NEW	$474,321
														Subtotal = $474,321

Grand Total All Awards = $474,321

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The Role of Slc25a1 in Acute Pro-inflammatory Activation of Microglia/Macrophages Post-Traumatic Brain Injury

Award Number: R01NS150283

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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