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Role of alcohol adapted Kupffer cells in the progression and resolution of ALD

Award Number: R01AA012863
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: 09/27/2000
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Role of alcohol adapted Kupffer cells in the progression and resolution of ALD - PROJECT SUMMARY Alcohol-associated liver disease (ALD) is a major world-wide health problem that accounts for approximately 40,000 deaths per year in the US. A major cause of death in ALD is the onset of an acute liver failure event called alcohol-associated hepatitis (AH). The mechanisms that cause the onset of AH in patients with ALD are unknown. The most important treatment for ALD is alcohol abstinence. Unfortunately, some people with ALD who stop drinking fail to adequately improve in terms of liver function or fibrosis. Again, the mechanisms leading to incomplete disease resolution after abstinence are unknown. Liver macrophages, including Kupffer cells and infiltrating macrophages, play a central role in regulating liver function during ALD but how they contribute to the onset of AH and what role they play in the outcome of liver disease following alcohol abstinence is unknown. We recently developed a new western diet alcohol (WDA) model of ALD that reproduces features of human alcohol- associated steatohepatitis in mice. Using single cell RNA sequencing, we have identified alcohol specific Kupffer cell subsets and assessed the function of these by selectively ablating them using diphtheria toxin receptor techniques. During alcohol exposure, KC ablation resulted in liver failure with hepatocytes de-differentiating into a progenitor-like phenotype very similar to the situation in human AH. This result demonstrates that KCs play a previously unrecognized role in maintaining differentiated hepatocyte function during chronic alcohol exposure. The overall hypothesis of this proposal is that during alcohol exposure, KCs produce signals, such as exosomal Let-7, that help to maintain hepatocytes in their differentiated state. Loss of KCs or KC function can trigger an AH-like loss of liver function. Upon alcohol cessation, KCs are also required for resumption of liver homeostasis and fibrosis resolution. Loss of KC subsets can delay recovery and suppress resolution of ALD fibrosis. In the current proposal we will determine how specific KC and IM subsets regulate hepatocyte function during alcohol exposure, how they change and function upon cessation of alcohol consumption, and how this information can be used to improve liver function and enhance recovery from ALD. We will achieve these goals with the following specific aims. (1) To determine the functions of KC and IM subsets in a mouse model of ALD, (2) to determine how Kupffer cell loss promotes hepatocyte transition to a progenitor-like state, and (3) to assess the role of MΦ subsets in fibrosis development and resolution after alcohol cessation. Understanding the factors that regulate the presence and function of alcohol- specific KC subsets would provide the opportunity to develop macrophage-based therapies to reverse liver failure in patients with AH and accelerate recovery in patients with ALD who cease alcohol consumption.


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 = $602,586 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	22	4/24/2025	NON-COMPETING CONTINUATION	$602,586
														Subtotal = $602,586

Issue Date FY: 2024 ( Subtotal = $602,586 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	002	21	2/29/2024	NON-COMPETING CONTINUATION	$542,327
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	003	21	5/20/2024	NON-COMPETING CONTINUATION	$60,259
2024	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	001	20	2/6/2024	COMPETING CONTINUATION	$10,024
2024	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	19	2/6/2024	NON-COMPETING CONTINUATION	-$10,024
														Subtotal = $602,586

Issue Date FY: 2023 ( Subtotal = $600,610 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	001	20	5/5/2023	COMPETING CONTINUATION	$600,610
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	002	20	9/19/2023	COMPETING CONTINUATION	$0
2023	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	19	4/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $600,610

Issue Date FY: 2021 ( Subtotal = $262,390 )
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Alcohol Research Programs	000	19	7/22/2021	NON-COMPETING CONTINUATION	$262,390
														Subtotal = $262,390

Issue Date FY: 2020 ( Subtotal = $260,403 )
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Alcohol Research Programs	000	18	7/22/2020	NON-COMPETING CONTINUATION	$260,403
														Subtotal = $260,403

Issue Date FY: 2019 ( Subtotal = $258,472 )
2019	2019	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Alcohol Research Programs	000	17	8/26/2019	COMPETING CONTINUATION	$258,472
														Subtotal = $258,472

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Alcohol Research Programs	000	16	7/5/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $516,577 )
2016	2016	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	16	2/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$516,577
														Subtotal = $516,577

Issue Date FY: 2015 ( Subtotal = $501,081 )
2015	2015	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	15	3/3/2015	NON-COMPETING CONTINUATION	$501,081
														Subtotal = $501,081

Issue Date FY: 2014 ( Subtotal = $501,081 )
2014	2014	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	14	2/26/2014	NON-COMPETING CONTINUATION	$501,081
														Subtotal = $501,081

Issue Date FY: 2013 ( Subtotal = $480,417 )
2013	2013	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	001	13	5/23/2013	NON-COMPETING CONTINUATION	$15,497
2013	2013	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	13	2/1/2013	NON-COMPETING CONTINUATION	$464,920
														Subtotal = $480,417

Issue Date FY: 2012 ( Subtotal = $516,577 )
2012	2012	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	002	12	3/8/2012	COMPETING CONTINUATION	$516,577
2012	2010	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	001	11	3/6/2012	SUPPLEMENT FOR EXPANSION	$0
2012	2009	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	11	3/6/2012	NON-COMPETING CONTINUATION	$0
2012	2009	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Trans-NIH Recovery Act Research Support	003	11	5/7/2012	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $516,577

Issue Date FY: 2011 ( Subtotal = $0 )
2011	2009	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	11	9/8/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $460,245 )
2010	2010	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	000	11	4/12/2010	SUPPLEMENT FOR EXPANSION	$460,245
														Subtotal = $460,245

Issue Date FY: 2009 ( Subtotal = $589,985 )
2009	2009	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Trans-NIH Recovery Act Research Support	003	11	9/18/2009	SUPPLEMENT FOR EXPANSION	$129,740
2009	2009	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	002	11	9/1/2009	NON-COMPETING CONTINUATION	$460,245
2009	2008	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Alcohol Research Programs	000	9	8/14/2009	NON-COMPETING CONTINUATION	-$157,668
2009	2008	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Alcohol Research Programs	001	10	8/14/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$157,668
														Subtotal = $589,985

Issue Date FY: 2008 ( Subtotal = $501,982 )
2008	2008	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Alcohol Research Programs	000	9	8/25/2008	NON-COMPETING CONTINUATION	$501,982
														Subtotal = $501,982

Issue Date FY: 2007 ( Subtotal = $500,149 )
2007	2007	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Alcohol Research Programs	000	8	8/27/2007	NON-COMPETING CONTINUATION	$500,149
														Subtotal = $500,149

Issue Date FY: 2006 ( Subtotal = $501,870 )
2006	2006	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Alcohol Research Programs	000	7	8/23/2006	NON-COMPETING CONTINUATION	$452,958
2006	2006	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Alcohol Research Programs	001	7	9/30/2006	SUPPLEMENT FOR EXPANSION	$48,912
														Subtotal = $501,870

Issue Date FY: 2005 ( Subtotal = $450,379 ) (Continued on the next page)
Grand Total All Awards = $9,597,390

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Role of alcohol adapted Kupffer cells in the progression and resolution of ALD

Award Number: R01AA012863

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: 09/27/2000

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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