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Unusual mechanisms of metal regulation in bacteria: from single molecules to single cells to cell communities

Award Number: R01GM109993
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: 07/01/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Unusual mechanisms of metal regulation in bacteria: from single molecules to single cells to cell communities - Defining how cells regulate the uptake and efflux of transition metals such as Zn is a key component in elucidating cellular mechanisms of metal homeostasis. Bacterial model systems provide paradigms for understanding regulation mechanisms. In E. coli, the Zn2+-responsive metalloregulator ZntR senses Zn excess and activates Zn efflux systems (e.g., ZntA), while Zur senses Zn sufficiency and represses Zn uptake systems (e.g., ZnuABC), to keep this essential metal at appropriate physiological levels in the cell. Past research has provided significant insights into the structure, function, and mechanism of the protein players in regulating cellular metal concentrations, including metalloregulators, and metal uptake/efflux transporters, etc. Yet, many mechanistic pathways are still poorly understood, especially regarding spatially and temporally coordinated interactions among proteins and/or DNA that can reside at different locations in the cell. The long-term goal here is to understand how metal regulation in the cell can be manipulated for preventive and therapeutic purposes. Toward this goal, the PI has established an internationally recognized and unique research program that applies and develops advanced single-molecule/single-cell imaging approaches to interrogate and understand the mechanisms of bacterial metal regulation both in vitro and in live cells, which are further enhanced by bulk biochemical/biophysical and protein/genetic engineering approaches and by established collaborations with biologists and engineers. The research has led to the discoveries of first-of-their-kind mechanisms of metal- responsive transcriptional regulation and metal efflux. The objective of this renewal is to advance the study and understanding of bacterial metal regulation from single molecules and single cells toward cell communities, comprising three aims that focus on Zn regulation in E. coli: (1) define a “through-DNA” mechanism for Zn uptake- vs-efflux regulation; (2) define the mechanism of ZnuABC for Zn uptake in the cell; and (3) dissect cell-cell interactions in Zn homeostasis within bacterial communities. The research is significant because it will provide novel mechanistic insights into: how metalloregulators can act on each other on DNA, beyond the present paradigm of “set-point” mechanism; the spatiotemporal coordination of multicomponent Zn transporters for Zn uptake; and the cell-cell interactions in Zn homeostasis within a bottom-up cell community; and because these insights will deepen our understanding of cell biology of metals in general, including related processes in human cells, thus providing fundamental knowledge for identifying causes or developing preventions of diseases that involve similar regulation processes or for devising strategies to impair bacterial Zn homeostasis for antimicrobial treatments. The research is innovative because it generates novel mechanistic concepts in metal regulation, uptake/efflux, and emergent behaviors in microbial communities and because it applies novel single- molecule/cell imaging methods as well as microfluidic and optogenetic manipulations.


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 = $331,049 )
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	11	7/16/2025	NON-COMPETING CONTINUATION	$331,049
														Subtotal = $331,049

Issue Date FY: 2024 ( Subtotal = $382,248 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	003	10	8/7/2024	SUPPLEMENT FOR EXPANSION	$51,082
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	10	4/9/2024	NON-COMPETING CONTINUATION	$298,049
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	002	10	6/7/2024	NON-COMPETING CONTINUATION	$33,117
2024	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	8	4/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $382,248

Issue Date FY: 2023 ( Subtotal = $331,271 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	9	7/25/2023	COMPETING CONTINUATION	$331,271
														Subtotal = $331,271

Issue Date FY: 2022 ( Subtotal = $278,672 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	8	5/17/2022	NON-COMPETING CONTINUATION	$278,672
														Subtotal = $278,672

Issue Date FY: 2021 ( Subtotal = $405,584 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	7	4/1/2021	NON-COMPETING CONTINUATION	$405,584
														Subtotal = $405,584

Issue Date FY: 2020 ( Subtotal = $405,701 )
2020	2020	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	6	4/29/2020	NON-COMPETING CONTINUATION	$278,914
2020	2020	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	6	5/4/2020	SUPPLEMENT FOR EXPANSION	$126,787
														Subtotal = $405,701

Issue Date FY: 2019 ( Subtotal = $279,021 )
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	5	7/5/2019	COMPETING CONTINUATION	$279,021
2019	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	5/15/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $279,021

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	4/17/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $297,240 )
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	6/21/2017	NON-COMPETING CONTINUATION	$297,240
														Subtotal = $297,240

Issue Date FY: 2016 ( Subtotal = $297,290 )
2016	2016	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	3	6/17/2016	NON-COMPETING CONTINUATION	$297,290
														Subtotal = $297,290

Issue Date FY: 2015 ( Subtotal = $297,337 )
2015	2015	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	2	6/30/2015	NON-COMPETING CONTINUATION	$297,337
														Subtotal = $297,337

Issue Date FY: 2014 ( Subtotal = $297,381 )
2014	2014	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	1	7/1/2014	NEW	$297,381
														Subtotal = $297,381

Grand Total All Awards = $3,602,794

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Unusual mechanisms of metal regulation in bacteria: from single molecules to single cells to cell communities

Award Number: R01GM109993

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: 07/01/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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