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Alcohol and Monocyte Signaling

Award Number: R01AA011576
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: 04/01/1998
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Alcohol and Monocyte Signaling - ABSTRACT Alcohol use is associated with both pro-inflammatory and immunosuppressive effects; however, cellular and molecular mechanisms or therapeutic interventions to normalize immune disturbances caused by alcohol are yet to be explored. Increased pro-inflammatory responses in the monocyte/macrophage and neutrophil populations are complicated by immune exhaustion leading to poor clinical outcomes in alcohol-associated hepatitis (AH). Recent studies described “trained immunity” that is characterized by long-term epigenetic reprogramming of innate immune cells by an infection or host factors such as, potentially, alcohol use. Our preliminary data suggest that alcohol induces features of “trained immunity” that is characterized by enhanced pro-inflammatory responses to subsequent insults. Thus, we hypothesize that chronic and/or binge alcohol use result in trained immunity in monocytes/macrophages and neutrophils and this contributes to exacerbated inflammatory responses in AH. Emerging evidence suggests that trained immunity is a result of immunometabolic and epigenetic programming of innate immune cells including bone marrow precursors. Consistent with this, we found increased utilization of glycolysis as opposed to OXPHOX in PBMCs of patients with AH. Thus, we hypothesize that alcohol-induced trained immunity is mediated by immunometabolic reprogramming. Our preliminary results also show altered metabolic profile in mice, specifically when challenged with LPS. We postulate that by identifying key alcohol-induced immunometabolic and epigenetic events, we can design targets for reversal of dysregulated innate immunity in AH. Our Aims are #1: To investigate the effects of alcohol use on features of trained immunity in mouse models and in human alcohol-associated hepatitis (AH) by a) Evaluating “trained immunity” in bone marrow granulocyte-monocyte progenitors (BM-GMP) and in liver neutrophils and monocyte/macrophages (Mo/Mφ) in alcohol “trained mice” after an LPS challenge; b) Identifying epigenetic features of trained immunity in liver neutrophil and Mo/Mφ populations and BM-GMP by snRNA+scATAC seq, and determine specific gene activation/repression marks by ChIP-qPCR; c) Characterizing the phenotypic and epigenetic signature of “trained immunity” in circulating neutrophil and Mo/Mφ populations in AH patients. #2: To identify the immunometabolic signature in “alcohol trained” mice after an LPS challenge and in humans with AH; and #3: To evaluate underlying mechanisms by which alcohol induces metabolic reprogramming and trained immunity by a) Assessing the role of the cellular energy sensor “PAS Kinase” in in vivo models of alcohol-induced trained immunity in mice; b) Restoring immune cell functionality by modulating specific immunometabolic receptors (SUCNR1, OXGR1), and immune checkpoint receptors (PD-1); c) Targeting key epigenetic regulators (HDAC9) in restoration of alcohol-induced trained immunity. Results from this proposal will provide novel insights into alcohol-induced immunometabolic and epigenetic alterations that can lead to “trained immunity” and thereby derail immune responses even after stopping alcohol use.


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 = $904,503 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	23	4/2/2026	NON-COMPETING CONTINUATION	$904,503
														Subtotal = $904,503

Issue Date FY: 2025 ( Subtotal = $909,344 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	001	22	8/26/2025	SUPPLEMENT FOR EXPANSION	$284,542
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	22	5/15/2025	NON-COMPETING CONTINUATION	$624,802
														Subtotal = $909,344

Issue Date FY: 2024 ( Subtotal = $597,407 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	21	4/24/2024	COMPETING CONTINUATION	$597,407
														Subtotal = $597,407

Issue Date FY: 2023 ( Subtotal = -$62,528 )
2023	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	20	9/18/2023	NON-COMPETING CONTINUATION	-$62,528
														Subtotal = -$62,528

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	20	3/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $393,750 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	002	20	5/1/2020	NON-COMPETING CONTINUATION	$393,750
2020	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	001	19	11/30/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$57,353
2020	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Alcohol Research Programs	000	18	11/30/2019	NON-COMPETING CONTINUATION	-$57,353
														Subtotal = $393,750

Issue Date FY: 2019 ( Subtotal = $376,875 )
2019	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	002	19	9/23/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$194,496
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Alcohol Research Programs	000	18	3/8/2019	NON-COMPETING CONTINUATION	$376,875
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Alcohol Research Programs	001	18	9/23/2019	NON-COMPETING CONTINUATION	-$194,496
														Subtotal = $376,875

Issue Date FY: 2018 ( Subtotal = $376,875 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Alcohol Research Programs	001	17	5/24/2018	NON-COMPETING CONTINUATION	$37,688
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Alcohol Research Programs	000	17	3/21/2018	NON-COMPETING CONTINUATION	$339,187
														Subtotal = $376,875

Issue Date FY: 2017 ( Subtotal = $376,875 )
2017	2017	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Alcohol Research Programs	001	16	7/3/2017	NON-COMPETING CONTINUATION	$37,688
2017	2017	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Alcohol Research Programs	000	16	3/29/2017	NON-COMPETING CONTINUATION	$339,187
														Subtotal = $376,875

Issue Date FY: 2016 ( Subtotal = $376,875 )
2016	2016	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	15	3/22/2016	COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2012 ( Subtotal = $547,521 )
2012	2012	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	14	3/29/2012	NON-COMPETING CONTINUATION	$547,521
														Subtotal = $547,521

Issue Date FY: 2011 ( Subtotal = $549,958 )
2011	2011	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	003	13	9/12/2011	SUPPLEMENT FOR EXPANSION	$2,500
2011	2011	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	002	13	9/9/2011	SUPPLEMENT FOR EXPANSION	$102,587
2011	2011	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	001	13	7/5/2011	NON-COMPETING CONTINUATION	$30,988
2011	2011	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	13	3/15/2011	NON-COMPETING CONTINUATION	$413,883
														Subtotal = $549,958

Issue Date FY: 2010 ( Subtotal = $449,299 )
2010	2010	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	12	3/30/2010	NON-COMPETING CONTINUATION	$449,299
														Subtotal = $449,299

Issue Date FY: 2009 ( Subtotal = $453,517 )
2009	2009	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	11	4/2/2009	NON-COMPETING CONTINUATION	$453,517
														Subtotal = $453,517

Issue Date FY: 2008 ( Subtotal = $462,704 )
2008	2008	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Alcohol Research Programs	000	10	4/14/2008	COMPETING CONTINUATION	$462,704
														Subtotal = $462,704

Issue Date FY: 2007 ( Subtotal = $374,385 )
2007	2007	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL AT WORCESTER	55 LAKE AVENUE NORTH	WORCESTER	MA	01605	WORCESTER	USA	Alcohol Research Programs	000	9	1/23/2007	NON-COMPETING CONTINUATION	$374,385
														Subtotal = $374,385

Issue Date FY: 2006 ( Subtotal = $385,566 )
2006	2006	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL AT WORCESTER	55 LAKE AVENUE NORTH	WORCESTER	MA	01605	WORCESTER	USA	Alcohol Research Programs	000	8	1/24/2006	NON-COMPETING CONTINUATION	$385,566
														Subtotal = $385,566

Issue Date FY: 2005 ( Subtotal = $394,845 )
2005	2005	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL AT WORCESTER	55 LAKE AVENUE NORTH	WORCESTER	MA	01605	WORCESTER	USA	Alcohol Research Programs	000	7	1/19/2005	NON-COMPETING CONTINUATION	$394,845
														Subtotal = $394,845

Issue Date FY: 2004 ( Subtotal = $394,845 )
2004	2004	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL AT WORCESTER	55 LAKE AVENUE NORTH	WORCESTER	MA	01605	WORCESTER	USA	Alcohol Research Programs	000	6	1/31/2004	NON-COMPETING CONTINUATION	$394,845
														Subtotal = $394,845

Issue Date FY: 2003 ( Subtotal = $394,845 )
2003	2003	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL AT WORCESTER	55 LAKE AVENUE NORTH	WORCESTER	MA	01605	WORCESTER	USA	Alcohol Research Programs	000	5		COMPETING CONTINUATION	$394,845
														Subtotal = $394,845

Grand Total All Awards = $9,703,783

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Alcohol and Monocyte Signaling

Award Number: R01AA011576

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: 04/01/1998

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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