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The pathophysiological function of PNPLA3-148M variant in alcohol-induced liver injury

Award Number: R01AA028506
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: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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The pathophysiological function of PNPLA3-148M variant in alcohol-induced liver injury - Project Summary Alcohol-related liver disease (ALD) is a very common health problem among alcohol drinkers. Multiple genome-wide association studies have reproducibly identified a single nucleotide polymorphism (rs738409, C→G) in the human patatin-like phospholipase domain containing 3 (PNPLA3) gene, which results in isoleucine (I) to methionine (M) substitution at amino acid 148, as the most significant gene variant associated with a broad spectrum of ALD ranging from steatosis, hepatitis, to cirrhosis to date. PNPLA3 is a lipid droplet-associated protein that is most abundantly expressed in human liver, which has been shown to have triglyceride lipase and retinyl palmitate hydrolase activities. However, the pathophysiology of the 148M variant of PNPLA3 in the liver remains largely unclear. In this project, we have developed transgenic mouse models for both variants of human PNPLA3 and validated the key features of human ALD in the 148M mouse model. We aim to further address the molecular underpinning of the 148M mutation in the alcohol-induced hepatic inflammation and fibrosis using both cell and animal models. It is expected that the mechanistic investigation in this application will provide direct evidence of the causal relationship between the 148M variant and the associated liver pathology. Altogether, we believe that this project is highly significant and innovative.


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: 2025 ( Subtotal = $446,640 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	000	4	4/28/2025	NON-COMPETING CONTINUATION	$446,640
														Subtotal = $446,640

Issue Date FY: 2024 ( Subtotal = $446,271 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	000	3	3/13/2024	NON-COMPETING CONTINUATION	$401,643
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	001	3	5/27/2024	NON-COMPETING CONTINUATION	$44,628
														Subtotal = $446,271

Issue Date FY: 2023 ( Subtotal = $445,912 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	000	2	4/3/2023	NON-COMPETING CONTINUATION	$445,912
														Subtotal = $445,912

Issue Date FY: 2022 ( Subtotal = $460,191 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	001	1	6/3/2022	NEW	$2,925
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Alcohol Research Programs	000	1	4/25/2022	NEW	$457,266
														Subtotal = $460,191

Grand Total All Awards = $1,799,014

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The pathophysiological function of PNPLA3-148M variant in alcohol-induced liver injury

Award Number: R01AA028506

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: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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