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Mechanistic studies of prokaryotic and eukaryotic nitrate/nitrite transport

Award Number: R01GM126626
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: 01/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Mechanistic studies of prokaryotic and eukaryotic nitrate/nitrite transport - Project Summary Recent studies suggest that nitrate and nitrite molecules have profound beneficial effects to human health, though they were thought to be cancerous since 1970s. To maximize their pharmaceutical potential, we need to first understand how nitrate and nitrite circulate in humans. Such circulation depends on two critical events: active accumulation of nitrate mediated by sialin transporters in salivary glands, as well as nitrate uptake and nitrite secretion by commensal bacteria in the mouth. Thus, nitrate/nitrite molecules have to cross different cellular membranes multiple times, before being used by humans. These translocation processes are mediated by a group of membrane proteins called nitrate transporters. To understand how these transporters function, we solved high-resolution crystal structures of NarK from E. coli, and further demonstrated that, surprisingly, NarK is a nitrate/nitrite exchanger. Despite the progress we made, the detailed molecular mechanisms of nitrate/nitrite translocation are still largely unknown. In this proposal, we aim to fill the knowledge gap by: 1) understand substrate selectivity and conformational flexibility using directed-mutagenesis of NarK, so to better understand the function of NarK at the molecular level; 2) obtain high-resolution structures of NarK in previously unobserved conformation, so we can reconstruct the complete transport cycle of NarK; 3) explore the structure-function relationship of human nitrate transporter sialin, so we will understand the similarities and differences among nitrate transporters from diverse species. Overall, upon completion of the proposal, we expect to expand our general understanding of the nitrate/nitrite transport, and shed light on the crucial roles that nitrate transporters (both eukaryotic and prokaryotic) play in nitrate/nitrite circulation. The knowledge gained here will facilitate potential drug development related to bacterial nitrate transporters and human sialin.


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: 2024 ( Subtotal = -$1 )
2024	2022	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	5	5/30/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2022 ( Subtotal = $304,687 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	5	11/8/2021	NON-COMPETING CONTINUATION	$274,218
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	001	5	7/20/2022	NON-COMPETING CONTINUATION	$30,469
														Subtotal = $304,687

Issue Date FY: 2021 ( Subtotal = $374,683 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	002	4	7/21/2021	SUPPLEMENT FOR EXPANSION	$71,915
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	001	4	2/11/2021	NON-COMPETING CONTINUATION	$30,277
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	4	11/13/2020	NON-COMPETING CONTINUATION	$272,491
														Subtotal = $374,683

Issue Date FY: 2020 ( Subtotal = $363,640 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	3	11/22/2019	NON-COMPETING CONTINUATION	$270,750
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	002	3	7/1/2020	SUPPLEMENT FOR EXPANSION	$62,806
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	001	3	3/5/2020	NON-COMPETING CONTINUATION	$30,084
														Subtotal = $363,640

Issue Date FY: 2019 ( Subtotal = $350,818 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	001	2	7/30/2019	SUPPLEMENT FOR EXPANSION	$49,711
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	2	11/16/2018	NON-COMPETING CONTINUATION	$301,107
														Subtotal = $350,818

Issue Date FY: 2018 ( Subtotal = $292,486 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Biomedical Research and Research Training	000	1	12/14/2017	NEW	$292,486
														Subtotal = $292,486

Grand Total All Awards = $1,686,313

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Mechanistic studies of prokaryotic and eukaryotic nitrate/nitrite transport

Award Number: R01GM126626

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: 01/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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