Friday, May 3, 2024 5/3/2024

Multi-modal rescue of pulmonary NRF2-insufficiency after burn and burn + inhalation injury to regulate innate immune dysfunction

Award Number: R01GM146134
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY The American Burn Association estimates that there are ~3,500 deaths each year from burn injuries. There are multiple influences on morbidity and mortality in burn patients, with inhalation injury among the most significant as it leads to increased susceptibility to opportunistic bacterial infections and the associated morbidity and mortality. A trifecta of clinical need is associated with this clinical problem: 1) we lack the ability to predict risk of infection, 2) we do not understand the mechanism of infectious risk, and 3) we are unable to restore a patient’s immune system to homeostasis after injury to enable adequate control of infectious agents. The overall objective of this application is to delineate mechanisms responsible for the cycle of uncontrolled inflammation following burn-injury to refine prediction models patient outcomes and to refine therapeutic approaches to restore immune homeostasis, thus decreasing susceptibility to infection and preventing the associated morbidity and mortality. We and others have demonstrated in human samples and mouse models that burn and burn + inhalation (B+I) injury generates the local and systemic release of numerous Damage-Associated Molecular Patterns (DAMPs). DAMPs promote interactions, via key immune regulators, such as mammalian Target of Rapamycin (mTOR) to induce reactive oxygen species (ROS), inflammatory cytokines, and chemokines which results in tissue damage and immune cell recruitment. Immune homeostasis is normally restored at least in part by the transcription factor Nuclear Factor-Erythroid-2-Related Factor (NRF2). Our preliminary data demonstrate that Nrf2-/- knockout mice have profound mortality after B+I injury. However, our preliminary data also demonstrate that while pulmonary immune cell NRF2 protein translation is rapidly increased after B+I in wildtype mice, it is not translocated to the nucleus. Thus, we hypothesize that the NRF2-mediated homeostasis following burn and B+I injury is insufficient, but that pharmacological activation of the NRF2 pathway has the potential to reduce acute immune dysfunction. Using our pre-clinical models of burn and B+I injury, we will define NRF2-specific mechanisms of acute immune dysfunction following burn or B+I injury and validate these findings in human cohorts within in our high-volume burn center. In addition, we will utilize microparticle technology to develop and characterize NRF2-driven therapy to improve post-injury immune dysfunction. As we appreciate that the response to burn and B+I is multifactorial, we will leverage this technology to combine NRF2 activation with a second approach and inhibit mTOR to provide a novel multimodal therapeutic approach. The efficacy of these approaches will be evaluated using our pre- clinical models of burn and B+I. We are uniquely poised to successful complete this proposal which will allow us to fill the existing knowledge gaps and improve long-term outcomes of burn and B+I patients.


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 = $287,658 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	4	4/15/2024	NON-COMPETING CONTINUATION	$287,658
														Subtotal = $287,658

Issue Date FY: 2023 ( Subtotal = $371,578 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	002	3	4/27/2023	NON-COMPETING CONTINUATION	$343,448
2023	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	003	1	7/2/2023	NEW	-$1
2023	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	1	3/15/2023	NEW	-$323,140
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	004	2	7/2/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	2	3/16/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$351,270
														Subtotal = $371,578

Issue Date FY: 2022 ( Subtotal = $323,141 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	1	6/22/2022	NEW	$323,141
														Subtotal = $323,141

Grand Total All Awards = $982,377

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Multi-modal rescue of pulmonary NRF2-insufficiency after burn and burn + inhalation injury to regulate innate immune dysfunction

Award Number: R01GM146134

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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