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Mechanisms of metabolic disease tolerance in sepsis

Award Number: R35GM133800
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Mechanisms of metabolic disease tolerance in sepsis - Project Summary/Abstract Sepsis is life-threatening organ dysfunction resulting from a dysregulated host response to infection. Two adaptation programs are set off during sepsis, one that mobilizes the immune system to enact resistance mechanisms directed against the pathogen, and one that tolerizes tissues against the harmful consequences of the response to infection. Recent studies support unique metabolic frameworks that mediate disease resistance and tolerance mechanisms. We are interested in the role of metabolites in mediating disease tolerance to sepsis, particularly how metabolites control the toxic mediators unleashed on tissues during sepsis. It has been well established that circulating hydrogen peroxide is elevated in human sepsis and negatively correlated with survival. Critically, antioxidant mechanisms such as cellular glutathione pools are rapidly depleted during sepsis due to excess hydrogen peroxide production. This, in turn, leads to high peroxide concentration inside cells, cell death, and peroxide release into the systemic circulation. We hypothesize that neutralizing extracellular hydrogen peroxide is crucial for establishing disease tolerance to sepsis. This proposal builds on our discovery in the previous funding period that branched-chain ketoacids (BCKAs) – metabolic products of branched-chain amino acid (BCAA) metabolism – function as antioxidants that directly neutralize hydrogen peroxide. Our studies further demonstrated the protective function of BCKAs in mouse sepsis models and indicated that BCKA levels are positively correlated with survival in human sepsis patients. Finally, we found that lactate dehydrogenase (LDHA) compromises BCKA antioxidant activity during sepsis. We will continue to focus on three major goals using a combination of biochemical engineering approaches, global and targeted metabolomics, and computational analysis methods. Goal 1: Stabilizing extracellular BCKAs to enhance sepsis survival. BCKAs are rapidly cleared from the circulation and utilized as cellular fuel, or alternatively depleted by LDHA during sepsis. We seek to engineer BCKAs and other small molecule derivatives in order to prevent cellular uptake and depletion during sepsis and enhance BCKA capacity to promote disease tolerance and survival. In Goal 2, we seek to establish circulating BCKAs and their derivatives as early prognostic biomarkers in sepsis. Only a handful of clinical biomarkers were shown to have prognostic value in sepsis, highlighting the unmet need in identifying reliable early biomarkers. We will take a human-centric reductionist approach to determine the extent to which BCAA-pathway metabolites, including BCKAs and their derivatives, could predict disease outcome across sepsis endotypes. And in Goal 3, we will identify broadly acting metabolites that enhance sepsis survival. We have established global metabolomics and computational prioritization methods in mouse sepsis models. We will leverage these pipelines towards characterizing metabolite landscapes in diverse sepsis patients and identify metabolites with broad protective activity. Together, we hope that our progress may unlock the potential of metabolite-mediated therapeutics for sepsis.


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 = $479,327 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	6	3/10/2026	COMPETING CONTINUATION	$479,327
														Subtotal = $479,327

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	5	10/30/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $427,750 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	5	5/1/2023	NON-COMPETING CONTINUATION	$427,750
														Subtotal = $427,750

Issue Date FY: 2022 ( Subtotal = $427,750 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	4	4/20/2022	NON-COMPETING CONTINUATION	$427,750
														Subtotal = $427,750

Issue Date FY: 2021 ( Subtotal = $427,750 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	4/16/2021	NON-COMPETING CONTINUATION	$427,750
														Subtotal = $427,750

Issue Date FY: 2020 ( Subtotal = $427,750 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	3/31/2020	NON-COMPETING CONTINUATION	$427,750
														Subtotal = $427,750

Issue Date FY: 2019 ( Subtotal = $427,750 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	6/26/2019	NEW	$427,750
														Subtotal = $427,750

Grand Total All Awards = $2,618,077

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Mechanisms of metabolic disease tolerance in sepsis

Award Number: R35GM133800

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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