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Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH

Award Number: R00AA030627
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: 09/21/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH - Project Summary/Abstract: Alcohol-associated hepatitis (AH) is a clinical manifestation of alcohol-associated liver disease (ALD) that has a very poor prognosis. Current treatments are ineffective and liver transplantation is the only long-term solution. The liver has the unique ability to regenerate post-injury but in ALD/AH this process becomes compromised. Mitochondria dysfunction is a hallmark of ALD and AH that can contribute to compromised liver regeneration. Mitochondria enriched with cardiolipin maintain the energy requirements (e.g., ATP) necessary for hepatocyte proliferation and liver regeneration. Preliminary data demonstrate that hepatic cardiolipin synthesis is compromised in clinical AH and experimental AH. Cardiolipin is required to maintain mitochondrial bioenergetics and undergoes oxidation and depletion in ALD compromising liver regeneration. However, treatment with cardiolipin or elamipretide (drug that prevents cardiolipin oxidation) can restore hepatocyte mitochondrial function and proliferation. The aim of this study is to determine if cardiolipin supplementation and preservation will promote liver regeneration via maintenance of ATP synthesis and prevention of hepatocyte apoptosis alleviating hepatic insufficiency in AH. This study uses pre-clinical animal models and human in vitro models of AH to assess the treatment efficacy of cardiolipin supplementation and preservation. Aim 1 will determine if mice with cardiolipin deficient hepatocytes have compromised liver regeneration due to loss of mitochondrial ATP synthesis in a model of AH. Aim 2 will test whether treatment with cardiolipin and elamipretide will enhance hepatic mitochondrial function, liver regeneration, and proliferating hepatocyte populations in an experimental animal model of AH. Aim 3 will identify cardiolipin species in human AH liver and plasma and assess their effect on hepatocyte proliferation and inflammatory responses in immune cells. The K99-phase (Aim 1) will provide training in assaying liver regeneration and mitochondrial function, sc-RNASeq analysis, and use of a mouse deficient in hepatocyte cardiolipin. This MOSAIC K99/R00 proposal will provide the training necessary (K99) to build a solid research foundation providing a pathway to independence as an independent researcher in the field of ALD and liver regeneration (R00). Findings from this study will identify a therapeutic strategy to treat AH via enhanced liver regeneration which could replace the only long-term treatment alternative, liver transplantation.


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 = $238,897 )
2026	2026	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Alcohol Research Programs	000	5	1/30/2026	NON-COMPETING CONTINUATION	$238,897
														Subtotal = $238,897

Issue Date FY: 2025 ( Subtotal = $244,023 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Alcohol Research Programs	000	4	11/21/2024	NON-COMPETING CONTINUATION	$219,621
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Alcohol Research Programs	001	4	8/14/2025	NON-COMPETING CONTINUATION	$24,402
														Subtotal = $244,023

Issue Date FY: 2024 ( Subtotal = $357,867 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Alcohol Research Programs	002	3	6/25/2024	EXTENSION WITH OR WITHOUT FUNDS	$108,868
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Alcohol Research Programs	003	3	7/23/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Alcohol Research Programs	001	3	6/10/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Alcohol Research Programs	000	3	12/18/2023	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $357,867

Grand Total All Awards = $840,787

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Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH

Award Number: R00AA030627

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: 09/21/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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