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Sulfide metabolism and signaling

Award Number: R35GM130183
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: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Sulfide metabolism and signaling - The liminal zone between host epithelium and gut microbiota is rich in sulfide conversations that are modulated by diet; their short- and long-range impacts on systemic H2S homeostasis represent a largely unexplored terrain ripe for discovery. The toxicity of H2S, first described as a noxious “acidic vapor” some 500 years ago, results from its inhibition of complex IV in the electron transport chain (ETC) and explains the ubiquitous presence of sulfide quinone oxidoreductase (SQOR) in mitochondria along with other sulfide oxidation pathway enzymes, for H2S disposal. The past cycle witnessed exciting advances, including the discovery of an unorthodox redox cofactor configuration, comprising an active site trisulfide, which affords the SQOR reaction an ~105-fold catalytic advantage, and characterization of the first clinical mutations in SQOR, which present with brain pathology typical of Leigh disease. We discovered that plasticity embedded in the mammalian ETC, which allows diversion of electrons to fumarate as a terminal acceptor when the capacity to use O2 is restricted by H2S. The ensuing reductive shift in the ETC, propagates beyond the mitochondrion via metabolic shuttles and redox cofactor pools, enhancing aerobic glycolysis, lipid biogenesis and reductive carboxylation in the Krebs cycle. In the next cycle, we will build on this exciting momentum as well as a wealth of preliminary data, introducing multi- omics approaches (metabolomics, RNA-Seq and CRISPRi) combined with cellular and genetic models of inducible SQOR deficiency (whole body or intestinal epithelium) to the rigorous biochemical foundations of our program. We will characterize the allosteric regulation of H2S biogenesis and clearance by metabolites identified from an unbiased screen, quantify the potential of H2S to tune O2 affinity of complex IV, and assess its impact on the hypoxic response. We will focus on the host-gut microbe interface, which we estimate accounts for ~70% of systemic sulfide homeostasis, and evaluate how its modulation by dietary methionine, microbial composition and host genotype influences brain pathology in control versus SQOR deficient mice. Advanced microscopic techniques, including live-cell imaging with biosensors to monitor ATP pools and redox shifts, will be used to elucidate H2S-induced changes to mitochondrial membrane potential, morphology and fusion. And we will uncover the molecular basis of the correlation between a graded decrease in gut reuterin (derived from Lactobacillus reuteri), and increasing tumor burden in colorectal cancer and the associated increase in host sulfur metabolites. We will continue to leverage the flexibility of the R35 funding mechanism for the sustained and innovative interrogation of the impact of H2S chemical biology in health and disease.


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: 2025 ( Subtotal = $436,552 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	003	7	12/13/2024	NON-COMPETING CONTINUATION	$436,552
2025	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	6	11/14/2024	COMPETING CONTINUATION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	002	6	12/11/2024	COMPETING CONTINUATION	$63,227
2025	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	5	12/11/2024	NON-COMPETING CONTINUATION	-$63,227
														Subtotal = $436,552

Issue Date FY: 2024 ( Subtotal = $537,906 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	6	12/14/2023	COMPETING CONTINUATION	$537,906
														Subtotal = $537,906

Issue Date FY: 2023 ( Subtotal = $390,000 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	5	12/8/2022	NON-COMPETING CONTINUATION	$351,000
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	5	4/5/2023	NON-COMPETING CONTINUATION	$39,000
														Subtotal = $390,000

Issue Date FY: 2022 ( Subtotal = $509,164 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	002	4	4/5/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	003	4	6/28/2022	NON-COMPETING CONTINUATION	$39,000
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	4	12/21/2021	NON-COMPETING CONTINUATION	$351,000
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	4	12/22/2021	SUPPLEMENT FOR EXPANSION	$119,164
														Subtotal = $509,164

Issue Date FY: 2021 ( Subtotal = $459,512 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	3	12/14/2020	NON-COMPETING CONTINUATION	$351,000
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	3	2/17/2021	NON-COMPETING CONTINUATION	$39,000
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	002	3	5/5/2021	SUPPLEMENT FOR EXPANSION	$69,512
														Subtotal = $459,512

Issue Date FY: 2020 ( Subtotal = $390,000 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	2	3/4/2020	NON-COMPETING CONTINUATION	$39,000
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	2	1/3/2020	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $390,000

Issue Date FY: 2019 ( Subtotal = $390,000 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	1	12/21/2018	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $3,113,134

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Sulfide metabolism and signaling

Award Number: R35GM130183

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: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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