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Role of MLKL in Alcohol-associated Liver Disease

Award Number: K99AA029146
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/22/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Role of MLKL in Alcohol-associated Liver Disease - Project summary The Candidate is a young investigator dedicated to developing an academic career focused on understanding the mechanisms by which ethanol disrupts balance between immune cell survival and death pathways. With a strong background in liver diseases and related innate immunity, the candidate has developed particular expertise in the use of in vivo and cell culture models to conduct the proposed studies. The Candidate’s current work has provided her with the opportunity to develop her own research program and begin her transition to independence. The Career Development Plan outlines 2-years of mentored training on technical skills and career development activities designed to promote the successful transition to independence. A 3-year program of independent scientific and career development after successful recruitment as an Assistant Professor position is also outlined. The Candidate’s Mentor has a proven track-record of excellent scientific productivity and successful mentorship and can provide the Candidate with a solid research environment in her lab. Research plan: Alcohol-associated liver disease (ALD) remains a major socioeconomic burden with high morbidity and mortality. Activation of innate immunity not only contributes to progression of ALD, but is also critical for resolution of injury. Appropriate regulation of pro-survival and pro-death pathways is critical to the ability of innate immune cells to rapidly respond to maintain liver homeostasis in ethanol-induced injury. MLKL-mediated necroptosis plays a dual role in tissue injury/repair. Whether MLKL-mediated necroptosis of immune cells is beneficial or detrimental in the context of ethanol is unknown. In preliminary work, Mlkl deficiency in myeloid cells exacerbated ethanol-induced injury, associated with increased ethanol-induced accumulation of hepatic macrophages and neutrophils. Importantly, we found that Gao-binge increased necrosis/necroptosis of hepatic F4/80+ cells, suggesting that MLKL may protect from ethanol-induced injury by promoting macrophage death and resolution of inflammation. Together, these data led us to hypothesize that myeloid cell-specific MLKL restricts ethanol- induced injury by regulating hepatic immune cell survival and death. To test this hypothesis, hepatic immune cell populations and death will be characterized by flow cytometric analysis of isolated NPCs from livers of Mlkl BM chimeras after Gao-binge. We will then challenge cell-specific knock-outs (LysM, Clec4f and MRP8 CRE crossed with Mlklfl/fl) to ethanol, to distinguish cell-specific contributions of MLKL to mALD. Further, a phospho-proteomics paired with targeted mechanistic approaches will be utilized to determine whether ethanol-mediated activation of MLKL is RIP3-dependent and/or RIP3-independent. Additionally, since neutrophils and neutrophil extracellular traps (NETs) are important in ALD, the project will further explore whether neutrophil-specific MLKL limits ethanol-induced injury by regulating NETs. Altogether, this proposal will provide a solid foundation for future mechanistic studies and clinical interventions for ethanol-induced injury and inflammation.


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: 2024 ( Subtotal = $0 )
2024	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	2	3/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $170,328 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	001	2	8/18/2022	NON-COMPETING CONTINUATION	$170,328
2022	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	1	11/18/2021	NEW	$0
														Subtotal = $170,328

Issue Date FY: 2021 ( Subtotal = $170,328 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	001	1	9/25/2021	NEW	$0
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	1	9/20/2021	NEW	$170,328
														Subtotal = $170,328

Grand Total All Awards = $340,656

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Role of MLKL in Alcohol-associated Liver Disease

Award Number: K99AA029146

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/22/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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