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Chemical biology approaches to probe signaling by protein lipidation

Award Number: R35GM119840
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: 07/15/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Chemical biology approaches to probe signaling by protein lipidation - Project Summary Protein lipidation is a dynamic post-translational modification (PTM) that affects subcellular trafficking, co-factor binding affinity, and membrane localization of proteins, which in turn influence downstream signaling cascades. In particular, cyclic S-acylation and -deacylation of proteins at specific cysteine residues is emerging as a key link between circulating lipid levels and the regulation of essential biological processes, including those involved in cellular growth, metabolism, and neurological health. In-depth study of this PTM, however, has proven technically difficult, in large part due to the paucity of selective, effective chemical inhibitors for the enzymes that catalyze its installation and removal. The proposed research program is designed to generate novel chemical technologies, namely small molecule probes and inhibitors, in the service of illuminating the involvement of regulated protein S-acylation in both normal and pathophysiological contexts. These goals will be realized through two complementary chemical and cellular biology research areas. One area will involve measuring, manipulating, and determining the targets of the “writers” of S-acylation, DHHCs. To do so, pan-active DHHC inhibitors will be identified using newly developed and optimized screening and selectivity profiling assays in combination with rationally and computationally designed molecules, as well as a library of putative inhibitors. Validated inhibitors and proteomics-based methods will then be used to identify the specific protein targets of DHHCs in live cells to more precisely describe their involvement in various disease states. The second research area will utilize our recently validated chemical tools to study the biological function of the “erasers” of S-acylation, APTs, with particular emphasis on the involvement of these enzymes in cellular redox homeostasis and metabolic disease. The expected outcome of this multidisciplinary research program is two-fold: generating a collection of chemical tools and assays for the study of this important PTM, and describing its biological function and influence in normal and disease states.


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 = $429,750 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	001	10	5/22/2025	NON-COMPETING CONTINUATION	$429,750
2025	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	9	11/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $429,750

Issue Date FY: 2024 ( Subtotal = $429,750 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	9	5/16/2024	NON-COMPETING CONTINUATION	$429,750
														Subtotal = $429,750

Issue Date FY: 2023 ( Subtotal = $593,957 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	001	8	6/15/2023	SUPPLEMENT FOR EXPANSION	$164,207
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	8	6/14/2023	NON-COMPETING CONTINUATION	$429,750
														Subtotal = $593,957

Issue Date FY: 2022 ( Subtotal = $429,750 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	7	6/2/2022	NON-COMPETING CONTINUATION	$429,750
														Subtotal = $429,750

Issue Date FY: 2021 ( Subtotal = $429,750 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	001	6	5/11/2021	COMPETING CONTINUATION	$429,750
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	003	6	9/4/2021	COMPETING CONTINUATION	$68,639
2021	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	5	5/10/2021	NON-COMPETING CONTINUATION	$0
2021	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	002	5	9/4/2021	NON-COMPETING CONTINUATION	-$68,639
														Subtotal = $429,750

Issue Date FY: 2020 ( Subtotal = $376,440 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	5	5/29/2020	NON-COMPETING CONTINUATION	$376,440
														Subtotal = $376,440

Issue Date FY: 2019 ( Subtotal = $376,440 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	4	5/21/2019	NON-COMPETING CONTINUATION	$376,440
														Subtotal = $376,440

Issue Date FY: 2018 ( Subtotal = $521,440 )
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	3	5/24/2018	NON-COMPETING CONTINUATION	$376,440
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	001	3	9/3/2018	SUPPLEMENT FOR EXPANSION	$145,000
														Subtotal = $521,440

Issue Date FY: 2017 ( Subtotal = $376,440 )
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	001	2	6/15/2017	NON-COMPETING CONTINUATION	$37,643
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	2	5/15/2017	NON-COMPETING CONTINUATION	$338,797
														Subtotal = $376,440

Issue Date FY: 2016 ( Subtotal = $376,440 )
2016	2016	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	1	7/11/2016	NEW	$376,440
														Subtotal = $376,440

Grand Total All Awards = $4,340,157

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Chemical biology approaches to probe signaling by protein lipidation

Award Number: R35GM119840

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: 07/15/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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