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MicroRNAs in Alcoholic Liver Disease

Award Number: R01AA020744
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: 09/10/2011
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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MicroRNAs in Alcoholic Liver Disease - PROJECT ABSTRACT Alcoholic liver disease (ALD) and alcoholic hepatitis (AH) are the leading causes of liver cirrhosis and liver- related death worldwide. MicroRNAs modulate the pathogenesis of ALD by regulating hepatocyte function, inflammatory cell activation and liver fibrosis. Our research revealed that alcohol-induced increase in miR-155 interferes with key elements in the pathogenesis of ALD including steatosis, liver damage and inflammation. Based on these data we hypothesize that miR-155 plays a cell-specific role in ALD both in hepatocytes and immune cells and represents a potential therapeutic target in ALD. We also discovered that circulating miR-155 is packaged in exosomes and that alcohol increases exosome release and our novel data show that alcohol- induced exosome production is attenuated in miR-155 deficient mice. We found that alcohol-induced upregulation of miR-155 promotes autophagy, both in macrophages and hepatocytes, by targeting key molecules in the autophagy pathway. Thus, we propose that exosome production is linked to impaired autophagy flux and it may represent a mechanism to maintain cellular homeostasis in alcohol exposed cells. The specific aims of this proposal will! 1) delineate the cell-specific role of miR-155 in ALD in hepatocytes and innate immune cells using hepatocyte- and bone marrow-derived cell-specific deletion of miR-155 (cre-lox recombination based) in vivo after chronic alcohol feeding (ALD) and acute binge on chronic alcohol (AH) in mice; 2) test the role of miR-155 in alcohol-induced exosome cargo and the biological effect of exosome- mediated transfer of miR-155 on hepatocyte-macrophage crosstalk; 3) investigate the effect of alcohol and miR-155 on the mechanistic inter-relationship between impaired autophagy flux and exosome production/biogenesis in hepatocytes and immune cells; and 4) evaluate the effect of inhibition of miR-155 on autophagy, exosome production and liver injury in a mouse model of ALD and AH using an AAV8-mediated miR-155 tough decoy to inhibit miR-155, in vivo. Our experiments will provide novel insights into key intracellular processes by which miR-155 regulates autophagy and exosome production for better understanding of the pathophysiology of alcoholic liver disease and alcoholic hepatitis.


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 = -$7,525 )
2026	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	10	12/17/2025	NON-COMPETING CONTINUATION	-$7,525
														Subtotal = -$7,525

Issue Date FY: 2023 ( Subtotal = $1,010,452 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	001	10	8/28/2023	NON-COMPETING CONTINUATION	$578,202
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	9	4/5/2023	SUPPLEMENT FOR EXPANSION	$432,250
														Subtotal = $1,010,452

Issue Date FY: 2022 ( Subtotal = $577,696 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	9	8/20/2022	NON-COMPETING CONTINUATION	$577,696
														Subtotal = $577,696

Issue Date FY: 2021 ( Subtotal = $577,199 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	8	7/26/2021	NON-COMPETING CONTINUATION	$577,199
														Subtotal = $577,199

Issue Date FY: 2020 ( Subtotal = $576,718 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	7	7/30/2020	NON-COMPETING CONTINUATION	$576,718
														Subtotal = $576,718

Issue Date FY: 2019 ( Subtotal = $587,355 )
2019	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	6	7/30/2019	COMPETING CONTINUATION	$587,355
														Subtotal = $587,355

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2015	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Alcohol Research Programs	000	5	12/13/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $405,447 )
2015	2015	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	5	6/11/2015	NON-COMPETING CONTINUATION	$405,447
														Subtotal = $405,447

Issue Date FY: 2014 ( Subtotal = $405,447 )
2014	2014	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	4	6/12/2014	NON-COMPETING CONTINUATION	$405,447
														Subtotal = $405,447

Issue Date FY: 2013 ( Subtotal = $388,528 )
2013	2013	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	001	3	9/17/2013	SUPPLEMENT FOR EXPANSION	$44,312
2013	2013	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	3	6/21/2013	NON-COMPETING CONTINUATION	$344,216
														Subtotal = $388,528

Issue Date FY: 2012 ( Subtotal = $370,125 )
2012	2012	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	2	6/27/2012	NON-COMPETING CONTINUATION	$370,125
														Subtotal = $370,125

Issue Date FY: 2011 ( Subtotal = $370,125 )
2011	2011	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	1	9/9/2011	NEW	$370,125
														Subtotal = $370,125

Grand Total All Awards = $5,261,567

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MicroRNAs in Alcoholic Liver Disease

Award Number: R01AA020744

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: 09/10/2011

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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