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TNF alpha and Recovery from Alcoholic Liver Injury

Award Number: R01AA010154
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: 05/05/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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TNF alpha and Recovery from Alcoholic Liver Injury - Morbidity and mortality in alcohol-related liver diseases (ALD) are caused by severe alcohol-induced steatohepatitis (SAH) and cirrhosis (AC). Effective therapies are lacking because the mechanisms driving the pathogenesis and progression of SAH and AC are unclear. This research program has evaluated the general hypothesis that bad outcomes of alcohol-induced liver injury result from deregulated repair mechanisms that cause defective regeneration of mature hepatocytes. Our prior results indicate that effective liver regeneration requires reactivating fetal programs to nurture the outgrowth of liver progenitors but then silencing these programs, so the liver matures appropriately. Thus, we will continue to evaluate the hypothesis that ALD progresses because mechanisms controlling when fetal programs are switched ON and OFF in adult liver cells are dysregulated. We have evidence that liver failure in human SAH results from the over-activation of fetal programs. Conversely, our pre-clinical data suggest that cirrhosis evolves when adult programs are not suppressed sufficiently for injured livers to regenerate. RNA Binding Proteins (RBPs) dynamically control the stability, translation, and splicing of mRNAs encoded by liver genes. Thus, we propose that RBPs critically control adult-fetal “switching” in hepatocytes during ALD. To identify the repertoire of RNA binding proteins, RNA splice variants, and liver genes that change in response to alcohol-induced liver injury, we coupled high- resolution sequencing of liver RNA with single-cell transcriptomics and chromatin accessibility analyses. ESRP2 was identified as one of the most down-regulated hepatocyte RBPs in human SAH. ESRP2 regulates the splicing of ~20% of hepatocyte RNAs, generating splice variants that encode functional differences in proteins that control hepatocyte proliferation and differentiation. We have reported that ESRP2 is critically important for switching on the adult program in developing livers and that over-expressing ESRP2 blocks adult liver regeneration. Our new data show that human SAH livers are enriched with fetal splice variants of ESRP2 targets that alter the activity and cellular localization of their encoded proteins. We reported that TNF and IL1 (critical cytokines in ALD pathogenesis) regulate both ESRP2 expression and adult-to-fetal “switching” in hepatocytes. Our ongoing studies indicate that manipulating ESRP2 exacerbates liver damage in mouse models of steatohepatitis, further supporting the concept that ESRP2 misregulation is an important driver of deregulated repair mechanisms in ALD. Iterative analyses of human liver samples and mouse models of liver injury and repair will continue during the next funding cycle. Based on present data, we will prioritize studies to determine how ESRP2-regulated RNA splicing events control hepatocyte responses to alcohol-induced injury, delineate how these adapted hepatocytes reconfigure other liver cell communities to dictate ALD outcomes, and define mechanisms that regulate ESRP2 expression, thereby revealing novel therapeutic targets to improve recovery from 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: 2025 ( Subtotal = $605,543 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Alcohol Research Programs	001	29	5/7/2025	COMPETING CONTINUATION	$605,543
2025	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Alcohol Research Programs	000	28	12/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $605,543

Issue Date FY: 2023 ( Subtotal = $496,125 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Alcohol Research Programs	000	28	7/20/2023	NON-COMPETING CONTINUATION	$496,125
														Subtotal = $496,125

Issue Date FY: 2022 ( Subtotal = $494,288 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	000	27	7/29/2022	NON-COMPETING CONTINUATION	$494,288
														Subtotal = $494,288

Issue Date FY: 2021 ( Subtotal = $492,507 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	000	26	7/30/2021	NON-COMPETING CONTINUATION	$492,507
														Subtotal = $492,507

Issue Date FY: 2020 ( Subtotal = $603,533 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	001	25	7/30/2020	NON-COMPETING CONTINUATION	$490,776
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	002	25	8/27/2020	NON-COMPETING CONTINUATION	$0
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	000	24	1/6/2020	COMPETING CONTINUATION	$112,757
														Subtotal = $603,533

Issue Date FY: 2019 ( Subtotal = $504,346 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	000	24	9/18/2019	COMPETING CONTINUATION	$504,346
														Subtotal = $504,346

Issue Date FY: 2009 ( Subtotal = $383,838 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	000	14	9/17/2009	COMPETING CONTINUATION	$383,838
														Subtotal = $383,838

Issue Date FY: 2008 ( Subtotal = $328,545 )
2008	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	000	13	7/16/2008	NON-COMPETING CONTINUATION	$328,545
														Subtotal = $328,545

Issue Date FY: 2007 ( Subtotal = $328,545 )
2007	2007	DUKE UNIVERSITY	BOX 104135	DURHAM	NC	27708	DURHAM	USA	Alcohol Research Programs	000	12	7/24/2007	NON-COMPETING CONTINUATION	$328,545
														Subtotal = $328,545

Issue Date FY: 2006 ( Subtotal = $338,358 )
2006	2006	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Alcohol Research Programs	000	11	8/17/2006	NON-COMPETING CONTINUATION	$338,358
														Subtotal = $338,358

Issue Date FY: 2005 ( Subtotal = $346,500 )
2005	2005	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Alcohol Research Programs	000	10	7/22/2005	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $346,500

Issue Date FY: 2004 ( Subtotal = $346,500 )
2004	2004	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Alcohol Research Programs	000	9	9/6/2004	COMPETING CONTINUATION	$346,500
														Subtotal = $346,500

Issue Date FY: 2003 ( Subtotal = $80,933 )
2003	2003	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Alcohol Research Programs	001	8		SUPPLEMENT FOR EXPANSION	$80,933
														Subtotal = $80,933

Issue Date FY: 2001 ( Subtotal = $334,057 )
2001	2001	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Alcohol Research Programs	000	8	7/23/2001	NON-COMPETING CONTINUATION	$334,057
														Subtotal = $334,057

Issue Date FY: 2000 ( Subtotal = $326,688 )
2000	2000	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Alcohol Research Programs	000	7	7/27/2000	NON-COMPETING CONTINUATION	$326,688
														Subtotal = $326,688

Issue Date FY: 1999 ( Subtotal = $319,532 )
1999	1999	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Alcohol Research Programs	000	6	7/8/1999	NON-COMPETING CONTINUATION	$319,532
														Subtotal = $319,532

Issue Date FY: 1998 ( Subtotal = $260,196 )
1998	1998	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Alcohol Research Programs	000	5	7/24/1998	NON-COMPETING CONTINUATION	$260,196
														Subtotal = $260,196

Grand Total All Awards = $6,590,034

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TNF alpha and Recovery from Alcoholic Liver Injury

Award Number: R01AA010154

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: 05/05/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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