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Xenobiotic-responsive hepatic long non-coding RNAs

Award Number: R01ES024421
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: 08/15/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Xenobiotic-responsive hepatic long non-coding RNAs - 7. Project Summary/Abstract Many industrial chemicals, environmental pollutants and other xenochemicals activate transcription factors belonging to the nuclear receptor superfamily, which leads to widespread genomic, epigenetic and transcriptional changes that disrupt key biological pathways and metabolic processes in liver and other tissues. The studies proposed focus on the liver nuclear receptor CAR (Constitutive Androstane Receptor; NR1I3), which is activated by structurally diverse xenochemicals and regulates transcription of hundreds of protein-coding genes important for processes such as xenobiotic metabolism, lipogenesis, glucose homeostasis, and inflammation, and has been implicated as a regulator of non-alcoholic fatty liver disease (NAFLD) development. We have discovered that xenobiotic agonists of CAR and other xenobiotic-responsive receptors induce or repress the transcription of several hundred nuclear-enriched long non-coding RNAs (lncRNAs) with epigenetic and gene regulatory potential, many of which have human orthologs. This proposal builds on these findings and on recent advances in liver cell zonation, single cell-based transcriptomic profiling, and gene co-expression network analysis to elucidate in an intact mouse liver model the effects of CAR-responsive lncRNAs on fatty liver disease induced by foreign chemical exposure. The studies proposed test the hypothesis that a subset of CAR-responsive lncRNAs control hepatic gene regulatory networks driving NAFLD and downstream pathologies, dysregulating processes such as lipid and carbohydrate metabolism, hepatic architecture and mitochondrial function in a liver cell type-specific and hepatic lobule zone-dependent manner. The work proposed uses TCPOBOP (1,4-bis[2-(3,5-dichloro-pyridyloxy)]benzene), a prototypic non- genotoxic chemical and CAR-specific agonist ligand, to address the seemingly paradoxical finding that persistent exposure to foreign chemical CAR activators induces NAFLD in mice fed normal chow diet, but suppresses NAFLD development in mice fed a high fat diet. These studies will elucidate the role of CAR, and the lncRNAs that it regulates, in fatty liver disease etiology and progression. Results obtained will give critical insight into the underlying mechanisms by which foreign chemicals dysregulate CAR-dependent metabolic pathways linked to NAFLD, which affects 25% of US adults and is a major cause of cirrhosis, hepatocellular cancer and liver failure. This work will refocus research efforts on xenochemical action to include mechanistic studies of single cell-based, spatially zonated gene regulatory networks and the non-coding transcriptome, and will serve as a paradigm for other foreign chemical-activated receptors that dysregulate gene expression in complex ways. Together, the proposed studies on CAR-responsive lncRNAs and their role in xenochemical- induced liver pathology may lead to new ways to prevent, diagnose or treat liver diseases induced by chemical exposure.


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 = $549,754 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	10	4/23/2024	NON-COMPETING CONTINUATION	$471,971
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	001	10	4/24/2024	SUPPLEMENT FOR EXPANSION	$77,783
														Subtotal = $549,754

Issue Date FY: 2023 ( Subtotal = $584,643 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	002	9	4/24/2023	SUPPLEMENT FOR EXPANSION	$77,783
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	8	12/20/2022	SUPPLEMENT FOR EXPANSION	$34,889
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	001	9	4/20/2023	NON-COMPETING CONTINUATION	$471,971
														Subtotal = $584,643

Issue Date FY: 2022 ( Subtotal = $471,971 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	8	4/29/2022	NON-COMPETING CONTINUATION	$471,971
														Subtotal = $471,971

Issue Date FY: 2021 ( Subtotal = $471,971 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	7	4/16/2021	NON-COMPETING CONTINUATION	$471,971
2021	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	002	6	5/30/2021	COMPETING CONTINUATION	$14,057
2021	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	001	5	5/30/2021	NON-COMPETING CONTINUATION	-$14,057
														Subtotal = $471,971

Issue Date FY: 2020 ( Subtotal = $471,971 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	002	6	7/6/2020	COMPETING CONTINUATION	$471,971
2020	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	001	5	6/26/2020	NON-COMPETING CONTINUATION	$0
2020	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	5	2/11/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $471,971

Issue Date FY: 2018 ( Subtotal = $403,884 )
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	5	4/25/2018	NON-COMPETING CONTINUATION	$403,884
														Subtotal = $403,884

Issue Date FY: 2017 ( Subtotal = $403,884 )
2017	2017	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	4	4/25/2017	NON-COMPETING CONTINUATION	$403,884
														Subtotal = $403,884

Issue Date FY: 2016 ( Subtotal = $403,884 )
2016	2016	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	3	4/25/2016	NON-COMPETING CONTINUATION	$403,884
														Subtotal = $403,884

Issue Date FY: 2015 ( Subtotal = $403,884 )
2015	2015	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	2	4/20/2015	NON-COMPETING CONTINUATION	$403,884
														Subtotal = $403,884

Issue Date FY: 2014 ( Subtotal = $403,884 )
2014	2014	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Environmental Health	000	1	8/15/2014	NEW	$403,884
														Subtotal = $403,884

Grand Total All Awards = $4,569,730

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Xenobiotic-responsive hepatic long non-coding RNAs

Award Number: R01ES024421

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: 08/15/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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