Friday, April 26, 2024 4/26/2024

Translational regulation in exposure biology: Xenobiotic-induced reprograming oftRNA modifications and selective translation of codon-biased response genes in rat and humanmodels

Award Number: R01ES026856
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

¿ DESCRIPTION (provided by applicant): The goal of this project is to explore a new systems-level mechanism by which cells respond to stresses and exposures by regulating translation. Cells respond to xenobiotic exposures by linking external stimuli to changes in cell phenotype through signal transduction, transcriptional regulation, and protein 2° modifications. Using a unique computational and analytical platform, we recently discovered a new mechanism of translational control of the cell stress response in yeast, in which toxicant-induced reprogramming of dozens of modified ribonucleosides in tRNA regulates protein levels by promoting the selective translation of codon-biased mRNAs representing families of stress-response genes. The goal of the proposed studies is to test the hypothesis that translational regulation of gene expression by stress-specific coordinated changes in the dozens of tRNA modifications plays a role in the response of cells and tissues to xenobiotic exposure in mammals. Abundant preliminary data in rat and mouse models, including tissue from the National Toxicology Program's DrugMatrix, supports this hypothesis, with strong evidence that xenobiotic- induced changes in tRNA modifications, as well as enzymes that modify tRNA, are essential regulators of stress responses in complex tissues. Here we will use human cell and rat exposure models to firmly place tRNA reprogramming as a translational regulator of the response to xenobiotics. Specifically, we hypothesize that exposure to xenobiotics promotes toxicant-specific changes in tRNA modification patterns, and that the reprogrammed tRNAs regulate protein levels by way of selective translation of codon-biased stress response transcripts. We will test these hypotheses in two aims. Aim 1 focuses on in vitro analysis of tRNA reprogramming and proteomic changes in human lung and liver cells exposed to a battery of alkylating and oxidizing agents that overlap with our published yeast exposure results. This provides a systematic comparison of yeast and mammalian cell responses. Aim 2 moves the in vitro studies of Aim 1 to the in vivo setting to test the hypothesis that the translational respons mechanism occurs in complex tissues. We first build on preliminary studies of arsenite exposure in rats using tissues from the NTP DrugMatrix to define the link between tRNA reprogramming and codon-biased translation with iTRAQ proteomics. We then test the translational control model in rats exposed to inhaled formaldehyde in collaboration with Drs. Melanie Doyle- Eisele and Ben Moeller (Lovelace Resp. Res. Inst.) and Jim Swenberg (UNC). We previously showed that pulmonary exposure to formaldehyde generates protein and DNA adducts in nasal epithelium but not more distant lung and liver tissues, so we anticipate seeing formaldehyde-induced tRNA reprogramming and codon- biased translation in nasal tissue but not lung or liver, with nasal tissue matching the in vitro studies of Aim 1. These studies will provide critical insights into a novel mechanism of cell response to xenobiotic stress with direct relevance to human exposures. Future studies will translate this model to human drug exposures and inflammatory diseases.


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: 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	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	001	3	1/29/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,994
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
														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 = $2,606,938

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Translational regulation in exposure biology: Xenobiotic-induced reprograming oftRNA modifications and selective translation of codon-biased response genes in rat and humanmodels

Award Number: R01ES026856

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer