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Developing chemical-proteomic tools to investigate cysteine oxidation

Award Number: R35GM134964
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: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Developing chemical-proteomic tools to investigate cysteine oxidation - Project Summary Various cellular processes generate reactive oxygen species (ROS) such as superoxide and hydrogen peroxide, which are key mediators of signaling pathways. Dysregulated redox homeostasis and ROS generation are hallmarks of diseases including cancer and age- associated degeneration. Primary cellular targets of ROS are cysteine thiols that form sulfenic, sulfinic, and sulfonic acids, as well as disulfides. ROS generation is localized to specific cellular regions, and are short-lived, necessitating spatiotemporal methods to study cysteine oxidation events. We have developed a chemical-proteomic strategy, termed isoTOP-ABPP, to study diverse oxidative cysteine modifications. To provide the necessary spatiotemporal readout, we will expand our current isoTOP-ABB platform by: (1) utilizing caged cysteine-reactive probes that can be activated rapidly by light for temporal control of cysteine labeling; and, (2) adapting the TurboID proximity biotinylation method to spatially localize our analysis to specific regions of the cell. We will apply these spatiotemporal readouts to two ROS-generating systems in the cell: (1) growth-factor mediated activation of NADPH oxidase (NOX); and, (2) inhibition of the electron transport chain (ETC) and mitochondrial superoxide dismutase. Epidermal growth factor (EGF) binding to EGFR, activates ROS release via NOX2. We aim to identify cysteine oxidation events proximal to NOX2 and characterize the role of these oxidation events on growth-factor signaling. In early studies, we identified a redox-active disulfide bond in a fatty-acid binding protein, FABP5, which is formed upon EGF stimulation of A431 cells. We will investigate the effects of disulfide-bond formation on the lipid-binding properties of FABP5, and downstream signaling pathways mediated by growth-factor stimulation. The mitochondria are highly redox-active organelles, and we aim to provide a comprehensive view of oxidation targets during mitochondrial dysfunction, by selectively enriching mitochondrial proteins prior to analysis. We will apply our optimized mitochondrial methods to interrogate cysteine oxidation in a C. elegans SOD-2 mutant with elevated mitochondrial ROS, and extended lifespan.


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 = $0 )
2025	2024	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $618,175 )
2024	2024	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	12/18/2023	NON-COMPETING CONTINUATION	$556,359
2024	2024	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	5/20/2024	NON-COMPETING CONTINUATION	$61,816
														Subtotal = $618,175

Issue Date FY: 2023 ( Subtotal = $618,175 )
2023	2023	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	12/21/2022	NON-COMPETING CONTINUATION	$556,359
2023	2023	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	001	4	4/5/2023	NON-COMPETING CONTINUATION	$61,816
														Subtotal = $618,175

Issue Date FY: 2022 ( Subtotal = $618,175 )
2022	2022	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	1/17/2022	NON-COMPETING CONTINUATION	$556,359
2022	2022	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	001	3	6/24/2022	NON-COMPETING CONTINUATION	$61,816
														Subtotal = $618,175

Issue Date FY: 2021 ( Subtotal = $618,175 )
2021	2021	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	2/12/2021	NON-COMPETING CONTINUATION	$61,818
2021	2021	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	12/15/2020	NON-COMPETING CONTINUATION	$556,357
														Subtotal = $618,175

Issue Date FY: 2020 ( Subtotal = $599,518 )
2020	2020	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	001	1	7/2/2020	SUPPLEMENT FOR EXPANSION	$250,000
2020	2020	BOSTON COLLEGE, TRUSTEES OF	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	12/27/2019	NEW	$349,518
														Subtotal = $599,518

Grand Total All Awards = $3,072,218

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Developing chemical-proteomic tools to investigate cysteine oxidation

Award Number: R35GM134964

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: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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