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Long Noncoding RNA H19 Mediating Alternative Splicing in ALD Pathogenesis

Award Number: R01AA030993
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Long Noncoding RNA H19 Mediating Alternative Splicing in ALD Pathogenesis - Project Summary Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD). ALD is a major public health issue in the US due to its rising incidence and prevalence. A better understanding of the mechanism of ALD pathogenesis is critical and may pave a way to identify potential therapeutic targets. H19 is a long noncoding RNA; its expression is highly upregulated in the liver of patients with ALD and ethanol-fed mice. However, the mechanism of H19 in ALD pathogenesis has not been fully explored. Our overarching objective of this grant application is to understand the mechanism of H19 mediated alcohol-induced liver injury. For specific aim#1, we plan to determine the molecular mechanism on alcohol induced hepatic H19 expression by focusing on two major pathways, epigenetic regulation via DNA methylation and transcriptional regulation by small heterodimer partner (SHP) and Early Growth Response 1 (EGR1). We will also employ our unique mouse models, H19 maternal specific knockout (H19Mat+/-) and liver specific H19 DNA methylation domain (DMD) knockout (H19DMDHep-/-) mice, to explore how loss of H19 function effects the hepatic phenotypes. In specific aim#2, we will determine the molecular mechanism of how H19 mediates alcohol-induced liver injury. We screened the H19 interacted proteins using RNA immunoprecipitation assay and found polypyrimidine tract binding protein 1 (PTBP1) binds to N-terminal of H19 RNA. PTBP1 is an RNA-binding protein to act primarily as repressive regulator of precursor mRNA (pre-mRNA) alternative splicing. We also found alcohol and H19 reduced PTBP1 expression levels and increased alternative splicing events. Therefore, we will determine the effect of PTBP1 deficiency on hepatic phenotypes in ethanol-fed mice using our newly generated PTBP1 liver specific knock out (Ptbp1Hep-/-) mice. Additionally, we identified that H19-PTBP1 axis mediates the splicing of its novel target gene betaine and homocysteine methyltransferase (BHMT), which was a critical enzyme in the methionine metabolism pathway. The splicing process led to a decrease in the BHMT protein coding variant and the reduction in BHMT protein expression led to a dysregulation of methionine metabolism, which contributed to alcohol induced liver injury. We will perform several mechanistic studies to determine the role of H19-PTBP1 axis in mediating BHMT alternate splicing. Taken together, we have developed animal and cellular models to mechanistically study both up and downstream pathways of H19-mediated ALD pathogenesis. This proposal is of significance and it may lead to potential therapeutic interventions by targeting H19-PTBP1-BHMT pathway in patients with ALD.


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 = $400,881 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	000	4	7/22/2026	NON-COMPETING CONTINUATION	$400,881
														Subtotal = $400,881

Issue Date FY: 2025 ( Subtotal = $400,881 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	000	3	8/14/2025	NON-COMPETING CONTINUATION	$400,881
														Subtotal = $400,881

Issue Date FY: 2024 ( Subtotal = $400,881 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	000	2	7/23/2024	NON-COMPETING CONTINUATION	$400,881
														Subtotal = $400,881

Issue Date FY: 2023 ( Subtotal = $414,381 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	000	1	8/15/2023	NEW	$414,381
														Subtotal = $414,381

Grand Total All Awards = $1,617,024

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Long Noncoding RNA H19 Mediating Alternative Splicing in ALD Pathogenesis

Award Number: R01AA030993

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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