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Defining the mechanisms of MSC extracellular vesicle modulation of microglia metabolism and bioenergetics in traumatic brain injury recovery

Award Number: R01NS133739
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: 09/08/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Defining the mechanisms of MSC extracellular vesicle modulation of microglia metabolism and bioenergetics in traumatic brain injury recovery - PROJECT SUMMARY Neuroinflammation plays a critical role in both the onset and progression of traumatic brain injury (TBI); however, most therapies are unable to address the multifaceted aspects. Following TBI, microglia become activated and produce inflammatory cytokines (including TNF-α and IL-6) that damage blood brain barrier (BBB), tight junctions, and lead to infiltration of peripheral immune cells such as neutrophils, monocytes, and T cells. Identification of new immunomodulatory strategies that target microglia and promote a neuroprotective environment is critical for treating this devastating disease. Mesenchymal stromal cells (MSCs) are a promising therapy for regenerative medicine applications due to their immunomodulatory function, which is mediated by secreted extracellular vesicles (MSC-EVs) that possess distinct surface composition and intravesicular cargo. Our group has demonstrated the ability of MSC-EVs to modulate cell-types involved in neuroinflammation such as microglia, T cells and pericytes. MSC-EVs are a promising therapeutic for TBI because they can i) have comparable immunomodulatory function to parent MSCs, ii) cross the BBB, and iii) address safety concerns associated with MSC delivery (i.e. tumorigenesis and thrombosis). Further, the targeting capabilities (mediated by surface signals) and MSC-EV cargo can be engineered through priming (preconditioning) of MSCs with different microenvironmental cues such as cytokines Interferon-gamma and Tumor necrosis factor alpha. However, there is a gap in knowledge over the role and mechanisms of MSC-EV modulation of microglia in the context of TBI and whether this effect can be enhanced through priming. The proposed work seeks to elucidate the mechanisms by which MSC-EVs modulate microglia with a specific focus on MSC-EV mitochondrial transfer. Our central hypothesis is that MSC-EVs produced from cytokine-primed MSCs will have greater functionality through modulation of microglia towards a more neuroprotective phenotype (e.g. reduced production of inflammatory cytokines and reactive oxygen species) and that this effect is mediated by MSC-EV derived mitochondrial transfer in vitro and in vivo. We will test this hypothesis in the following aims: 1) Define the mechanisms of mitochondrial transfer from MSC-EV on microglia metabolism, and 2) Assess MSC-EV therapeutic efficacy in a porcine TBI model. Successful completion of the proposed work will create a novel, tunable approach for targeting the brain’s immune system and treating TBI through a better understanding of MSC-EV mechanisms of action.


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 = $622,410 )
2026	2026	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/19/2026	NON-COMPETING CONTINUATION	$622,410
														Subtotal = $622,410

Issue Date FY: 2025 ( Subtotal = $621,942 )
2025	2025	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/28/2025	NON-COMPETING CONTINUATION	$621,942
														Subtotal = $621,942

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/30/2024	NEW	$0
2024	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/31/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $509,254 )
2023	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/8/2023	NEW	$509,254
														Subtotal = $509,254

Grand Total All Awards = $1,753,606

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Defining the mechanisms of MSC extracellular vesicle modulation of microglia metabolism and bioenergetics in traumatic brain injury recovery

Award Number: R01NS133739

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: 09/08/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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