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Regulatory Roles of Zinc Fluxes in Metalloprotein Occupancy and Cell Cycle Progression

Award Number: R01GM115848
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: 07/01/2015
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Regulatory Roles of Zinc Fluxes in Metalloprotein Occupancy and Cell Cycle Progression - PROJECT SUMMARY This project examimes the structure, spectroscopy, function, and mechanism of metallproteins that regulate cell cycle progresion in response to programmatic fluctuations in intracellular zinc concentration. Zinc fluxes have recently been discovered to be key regulatory events in human physiology, including cortical neuron function, immune response, fertilization, and insulin secretion. Despite its apparent roles in these profound physiologies, the biochemistry of zinc action is not well understood. Little is known regarding the inorganic chemistry of metalloproteins involved in the instructive mechanisms that mediate cellular responses to zinc fluxes, zinc trafficking pathways, or the role of specific metalloprotein receptors in signaling events. To interpret and eventually intervene in diseases caused by disruption of such pathways, we must first elucidate the fundamental molecular mechanisms of zinc-dependent switching events. While zinc has traditionally been viewed as a static cofactor involved in protein structure and enzyme catalysis, recent studies support the idea that zinc binding sites in regulatory proteins respond to transient fluctuations in zinc availability and are switched on and off in ways that regulate key cellular events. We will test the hypothesis that regulatory zinc fluxes exert instructive control over the mammalian cell cycle through specific, receptor- mediated processes. This hypothesis is based on multiple lines of evidence, including: (1) data showing fluctuations zinc distribution at various points in the cell cycle for single cells; (2) live cell imaging demonstrating the movement of waves of zinc; and (3) physicochemical approaches showing colocalization of zinc with specific factors. The overarching objective of this proposal is to use biochemical and spectroscopic approaches to understand how the influx and efflux of zinc exert control over the cell cycle. Chemicals tools to probe and control the concentration of zinc will be created to further our understanding of zinc physiology. In addition, we will leverage emerging techniques in X-ray absorption and emission spectroscopy, NMR, and mass spectrometry to understand the chemical environment of zinc and probe the zinc occupancy of zinc-containing proteins that regulate cell cycle progression. Taken together, the results from these studies will elucidate a robust role for zinc signaling fluxes during the cell cycle.


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 = $329,389 )
2025	2025	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	8	12/11/2024	NON-COMPETING CONTINUATION	$329,389
														Subtotal = $329,389

Issue Date FY: 2024 ( Subtotal = $407,788 )
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	002	7	8/30/2024	SUPPLEMENT FOR EXPANSION	$41,798
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	7	12/12/2023	NON-COMPETING CONTINUATION	$329,389
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	7	6/7/2024	NON-COMPETING CONTINUATION	$36,601
														Subtotal = $407,788

Issue Date FY: 2023 ( Subtotal = $365,990 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	6	12/9/2022	NON-COMPETING CONTINUATION	$329,389
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	6	2/15/2023	NON-COMPETING CONTINUATION	$36,601
														Subtotal = $365,990

Issue Date FY: 2022 ( Subtotal = $446,531 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	5	12/16/2021	COMPETING CONTINUATION	$446,531
2022	2018	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	001	4	1/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $446,531

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	4	4/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST EVANSTON	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	4	10/24/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $291,717 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST EVANSTON	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	4	4/25/2018	NON-COMPETING CONTINUATION	$291,717
														Subtotal = $291,717

Issue Date FY: 2017 ( Subtotal = $292,357 )
2017	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST EVANSTON	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	001	3	6/13/2017	NON-COMPETING CONTINUATION	$29,236
2017	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST EVANSTON	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	3	4/12/2017	NON-COMPETING CONTINUATION	$263,121
														Subtotal = $292,357

Issue Date FY: 2016 ( Subtotal = $361,217 )
2016	2016	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	001	2	7/18/2016	SUPPLEMENT FOR EXPANSION	$68,252
2016	2016	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	2	4/18/2016	NON-COMPETING CONTINUATION	$292,965
														Subtotal = $361,217

Issue Date FY: 2015 ( Subtotal = $293,544 )
2015	2015	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Biomedical Research and Research Training	000	1	6/19/2015	NEW	$293,544
														Subtotal = $293,544

Grand Total All Awards = $2,788,533

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Regulatory Roles of Zinc Fluxes in Metalloprotein Occupancy and Cell Cycle Progression

Award Number: R01GM115848

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: 07/01/2015

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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