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Translational regulation in exposure biology - Xenobiotic-induced reprograming of tRNA modifications and selective translation of codon-biased response genes in rat and human models

Award Number: R01ES026856
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Translational regulation in exposure biology - Xenobiotic-induced reprograming of tRNA modifications and selective translation of codon-biased response genes in rat and human models - ABSTRACT Human cells respond to xenobiotic exposures by altering gene expression, with the ~50 RNA modifications comprising the epitranscriptome emerging as key regulators of the stress response. We have developed unique RNA modification detection (LC-MS/MS, AQRNA-seq), tRNA gene expression (AQRNA-seq), and computational (Codon Analytics) technologies to show that yeast, rat livers, mice and cultured human cells respond to xenobiotic exposures with coordinated changes in the levels of tRNA modifications and tRNAs, to regulate codon-biased translation of important stress response proteins. Using liver from rats exposed to six drugs and toxicants in the NTP DrugMatrix program, we observed that 23 different tRNA modifications were uniquely altered in toxicant-, dose- and time-dependent manner after exposure. Among the changes, arsenite increased the level of queuosine (Q), a key tRNA wobble modification that decodes codons for four amino acids (His, Tyr, Asn, Asp). This behavior was recapitulated in human liver cells (HEPG2), with Q incorporation into tRNA in response to sodium arsenite required for cell viability, reactive oxygen species (ROS) detoxification, and mitochondrial function, and decreased Q levels promoting changes in translation. Similarly, the wobble U tRNA wobble base 5-methoxycarbonyl-methyluridine (mcm5U) was also increased in response to sodium arsenite in rat liver and HepG2 cells, with knockdown of the corresponding wobble U writer – ALKBH8 – promoting decreased cell viability, increased ROS, and changes in mitochondrial function. We have further shown that ALKBH8 defects disrupt the translation of selenocysteine (Sec)-containing glutathione peroxidases (GPXs) that detoxify ROS and promote mitochondrial function. In this renewal application, we will test the hypothesis of organ-specific tRNA reprogramming and codon-biased translation in rats and human cells exposed to arsenite and other toxicants, and then test the idea that whole blood and white blood cells (WBCs) serve as an accessible sampling compartment for human epitranscriptome biomarker studies.


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 = $446,906 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	000	9	6/18/2024	NON-COMPETING CONTINUATION	$446,906
														Subtotal = $446,906

Issue Date FY: 2023 ( Subtotal = $449,561 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	002	8	6/30/2023	NON-COMPETING CONTINUATION	$449,561
2023	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	001	7	12/14/2022	COMPETING CONTINUATION	$5,824
2023	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	000	6	12/14/2022	NON-COMPETING CONTINUATION	-$5,824
														Subtotal = $449,561

Issue Date FY: 2022 ( Subtotal = $465,482 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	000	7	8/30/2022	COMPETING CONTINUATION	$465,482
														Subtotal = $465,482

Issue Date FY: 2020 ( Subtotal = $333,101 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	000	6	8/21/2020	NON-COMPETING CONTINUATION	$333,101
														Subtotal = $333,101

Issue Date FY: 2019 ( Subtotal = $333,024 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	002	5	8/12/2019	NON-COMPETING CONTINUATION	$333,024
2019	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	000	2	1/29/2019	NON-COMPETING CONTINUATION	-$2,994
2019	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	001	3	1/29/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,994
														Subtotal = $333,024

Issue Date FY: 2018 ( Subtotal = $334,048 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	002	4	8/23/2018	NON-COMPETING CONTINUATION	$334,048
2018	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	001	3	6/8/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$307,414
2018	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	000	2	6/7/2018	NON-COMPETING CONTINUATION	-$307,414
														Subtotal = $334,048

Issue Date FY: 2017 ( Subtotal = $354,362 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	000	2	8/11/2017	NON-COMPETING CONTINUATION	$354,362
														Subtotal = $354,362

Issue Date FY: 2016 ( Subtotal = $337,360 )
2016	2016	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Environmental Health	000	1	8/17/2016	NEW	$337,360
														Subtotal = $337,360

Grand Total All Awards = $3,053,844

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Translational regulation in exposure biology - Xenobiotic-induced reprograming of tRNA modifications and selective translation of codon-biased response genes in rat and human models

Award Number: R01ES026856

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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