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Modulation of RNA Binding Proteins in Xenobiotic-induced Hepatotoxicity

Award Number: R01ES033709
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: 01/22/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Modulation of RNA Binding Proteins in Xenobiotic-induced Hepatotoxicity - Project Summary Approximately 33% of the nearly 700 workplace chemicals identified in the National Institute of Occupational Safety and Health (NIOSH) Pocket Guide are associated with hepatotoxicity. Several of these have been linked to increased liver disease mortality in workers in different occupational settings such as heavy construction equipment operators, chimney sweepers, and chemical workers. Xenobiotic-induced hepatotoxicity is characterized by oxidative stress, inflammation, and fibrosis, which, in later stages, may result in hepatic failure and hepatocellular carcinoma (HCC). While transcriptional perturbations have been implicated in inflammation and fibrosis; the role of post-transcriptional regulation in the development of xenobiotic-induced hepatic inflammation and fibrosis is unclear. The tristetraprolin (TTP) family of RNA binding proteins (RBPs) including zinc finger protein 36 (ZFP36) commonly referred to as TTP, zinc finger protein 36 like 1 (ZFP36L1), and zinc finger protein 36 like 2 (ZFP36L2), are the key players in post-transcriptional regulation of a large number of inflammation-relevant mRNAs. These proteins bind to AU-rich elements (AREs) on the 3’untranslated regions (3’UTRs) of target mRNAs and promote their decay. TTP family RBPs are dysregulated in human HCC. Industrial chemicals including chlorpyrifos, tetrachlorodibenzo-p-dioxin (TCDD), and carbon tetrachloride (CCl4), also dysregulate the expression of TTP family RBPs. However, the downstream molecular and cellular effects of these dysregulations on the host remain unknown. In this proposal, we will test our novel hypothesis that xenobiotic-induced dysregulation of TTP family RBPs expression results in altered post-transcriptional regulation that determines the pathogenesis of hepatic inflammation and fibrosis. We will use CCl4-induced liver inflammation and fibrosis as a model of hepatotoxicity and test our hypothesis through three specific aims. In Aim 1, we will employ liver-specific ablations of the three RBPs in mice and novel “omics” approaches to test the pathogenic mechanisms by which these RBPs regulate xenobiotic-induced liver inflammation and fibrosis. Aim 2 will characterize the cellular and molecular mechanisms by which TTP family RBPs regulate epithelial- mesenchymal transition, a lead cause of fibrosis and tumor metastasis, and finally, Aim 3 will test whether increasing the expression of TTP family RBPs in the liver protects against xenobiotic-induced hepatic inflammation and fibrosis. The overall goal of the proposed research is to understand the role of TTP family RBP mediated post-transcriptional regulation in the pathogenesis of xenobiotic-induced hepatotoxicity. Successful completion of the proposed studies will have a significant impact on the mechanistic understanding of the pathophysiology of xenobiotic-induced liver disease and the potential identification of TTP family RBPs as endogenous anti-inflammatory/anti-fibrotic proteins whose activity could be possibly enhanced to delay or prevent the onset of liver failure.


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: 2026 ( Subtotal = $459,895 )
2026	2026	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Environmental Health	000	3	2/18/2026	NON-COMPETING CONTINUATION	$459,895
														Subtotal = $459,895

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Environmental Health	000	2	1/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $459,895 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Environmental Health	001	2	1/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$459,895
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Environmental Health	003	2	8/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$354,620
2024	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Environmental Health	002	1	8/6/2024	NEW	-$354,620
2024	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Environmental Health	000	1	1/19/2024	NEW	$0
														Subtotal = $459,895

Issue Date FY: 2023 ( Subtotal = $464,386 )
2023	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Environmental Health	000	1	3/9/2023	NEW	$464,386
														Subtotal = $464,386

Grand Total All Awards = $1,384,176

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Modulation of RNA Binding Proteins in Xenobiotic-induced Hepatotoxicity

Award Number: R01ES033709

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: 01/22/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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