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Transcriptional and non-transcriptional function of IRF3 in ALD

Award Number: R01AA027456
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: 07/05/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Transcriptional and non-transcriptional function of IRF3 in ALD - ABSTRACT Chronic alcohol abuse underlies the pathogenesis of alcohol-associated liver disease (ALD), encompassed by a spectrum of pathologies, ranging from steatosis, to more severe forms of liver injury, including alcohol- associated hepatitis (AH), fibrosis, and cirrhosis. Acute AH has a very high mortality rate, with no effective therapeutic Patients with AH who exhibit stage 3-4 fibrosis have worse prognosis; however, treatment strategies do not include therapy for the resolution of fibrosis, representing an important unmet clinical need. Recruitment of innate immune cells to the liver and the regulation of their phenotype between pro-inflammatory/fibrogenic vs pro-resolution activity, impacts both disease progression and resolution. Hepatic stellate cells (HSC), the primary producer of extracellular matrix in the liver, are also regulated by innate immune pathways. During the previous granting cycle, we discovered that IRF3-dependent pathways, a component of host anti-viral responses, contribute to injury in murine models of ALD, NAFL/NASH and fibrosis. These data led us to ask the fundamental question: what is the mechanism by which metabolic/sterile liver diseases activate anti-viral signaling and can this be leveraged to develop novel therapeutics? We identified perturbations in homeostatic regulation of endogenous dsRNA in both immune cells and HSCs suggesting that endogenous dsRNAs are novel host-derived DAMPs that activate IRF3 signaling and contribute to the pathogenesis of ALD. IRF3 is classically recognized as a transcription factor essential for host anti-viral responses, but also has non-transcriptional activities. Using a novel knock-in mouse expressing an IRF3 protein that only exhibits non-transcriptional functions of IRF3 (Irf3S1/S1), we discovered that 1) IRF3-mediated apoptosis of innate immune cells recruited to the liver in response to Gao-binge ethanol increases inflammation and liver injury and 2) non-transcriptional functions of IRF3 restricted NFκB activity in a murine model of NAFL/NASH. Here we propose to extend our studies into IRF3 functions in pathogenesis of hepatic fibrosis in two specific aims: 1) Determine the contribution of the transcriptional and non-transcriptional IRF3 to murine models of hepatic fibrosis: Using Irf3-/-, Irf3S1/S1 and cell-specific deletions of Irf3, we will test the hypothesis that non-transcriptional activity of IRF3 contributes to recruitment of neutrophils to liver and enhances activation of HSCs in mice exposed to CCl4+ethanol or CDAA models of fibrosis. 2) Discover the cell intrinsic functions of IRF3 in the pathogenesis of fibrosis: Mechanistically, we will identify specific dsRNAs accumulating in cultured HSCs and neutrophils, interrogate perturbations in expression of RNA chaperones and dsRNA recognition molecules critical to IRF3 activation in fibrosis. Further, we will interrogate mechanisms for Irf3-dependent cell- cell interactions in fibrosis using human-iPSC 3-dimensional liver cultures. In summary, our studies will reveal novel cell-specific roles for non-transcriptional activity of IRF3 in hepatic fibrosis, as well as identify potential therapeutic targets that would prevent fibrosis and/or improve the resolution of fibrosis in patients with 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: 2026 ( Subtotal = $555,449 )
2026	2026	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	6	6/19/2026	NON-COMPETING CONTINUATION	$555,449
														Subtotal = $555,449

Issue Date FY: 2025 ( Subtotal = $555,449 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	5	8/5/2025	NON-COMPETING CONTINUATION	$555,449
														Subtotal = $555,449

Issue Date FY: 2024 ( Subtotal = $567,648 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	001	4	8/23/2024	COMPETING CONTINUATION	$567,648
2024	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	3	11/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $567,648

Issue Date FY: 2021 ( Subtotal = $640,878 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	3	7/12/2021	NON-COMPETING CONTINUATION	$479,934
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	001	3	7/16/2021	SUPPLEMENT FOR EXPANSION	$160,944
														Subtotal = $640,878

Issue Date FY: 2020 ( Subtotal = $639,933 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	001	2	9/9/2020	SUPPLEMENT FOR EXPANSION	$160,944
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	2	7/1/2020	NON-COMPETING CONTINUATION	$478,989
														Subtotal = $639,933

Issue Date FY: 2019 ( Subtotal = $491,942 )
2019	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	1	7/4/2019	NEW	$491,942
														Subtotal = $491,942

Grand Total All Awards = $3,451,299

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Transcriptional and non-transcriptional function of IRF3 in ALD

Award Number: R01AA027456

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: 07/05/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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