Thursday, April 18, 2024 4/18/2024

Impact of chronic alcohol consumption on the functional and epigenetic landscapes of monocytes and their progenitors

Award Number: R01AA028735
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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PROJECT SUMMARY Approximately ~7% of alcohol-consuming individuals engage in chronic heavy drinking (CHD), which is associated with increased susceptibility to infections as well as impaired wound healing and tissue repair resulting in poor post-operative outcomes. Evidence suggests that many of these defects are mediated by excessive inflammatory responses originating from myeloid cells, notably circulating monocytes and tissue- resident macrophages. These data were primarily generated from in vitro studies where monocytes from healthy donors or cell lines are treated high doses of ethanol. However, the mechanisms underlying the effects of CHD cannot be fully understood by in vitro studies because immune cells carry out their functions in a multicellular environment in which alcohol has widespread effects. Due to a lack of studies utilizing reliable in vivo models, our understanding of the mechanisms underlying aberrant inflammatory responses in the context of CHD remains incomplete. To address these knowledge gaps, we propose to leverage a rhesus macaque model of voluntary ethanol self-administration that accurately mirrors human physiology and recapitulates complex human drinking behavior. Using this model, our lab has recently demonstrated that CHD results in transcriptional and epigenetic rewiring of circulating monocytes and splenic macrophages, resulting in aberrant responses to LPS stimulation. However, the functional implications of this reprogramming and the epigenetic mechanisms controlling it remain unknown. Importantly, because monocytes are short-lived circulating cells under constant repopulation from the bone marrow, these observations suggest perturbations of the hematopoietic niche. Preliminary single-cell analyses of hematopoietic progenitors point to a shift in differentiation potential towards more mature myeloid progenitors with alcohol. However, a link between this observation in progenitor cells and their differentiated states in blood and tissue remains unclear. In this application, we propose to test the hypothesis that chronic alcohol consumption reprograms the epigenetic landscape of monocyte progenitors in the bone marrow giving rise to circulating monocytes poised towards a hyper- inflammatory response. We will first examine the impact of CHD on functional reprogramming of circulating monocytes, implementing assays to test their ability to migrate, phagocytose, and generate proper metabolic responses. We will next examine the effect of stimulation on the monocyte epigenetic landscape through assessment of chromatin accessibility and abundance of specific histone modifications. Finally, we will determine the effect of CHD on the differentiation potential, transcriptome activation, and epigenetic rewiring of bone marrow myeloid progenitors and integrate these data with those obtained from peripheral blood monocytes. Completion of this proposal will provide novel insight into the impact of CHD on myelopoiesis and mechanisms by which it compromised immunity and host defense as well as design interventions to mitigate these adverse events and improve immunological outcomes.


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: 2023 ( Subtotal = $460,235 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	002	5	7/28/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	001	5	7/27/2023	SUPPLEMENT FOR EXPANSION	$116,701
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	000	5	7/19/2023	NON-COMPETING CONTINUATION	$343,534
														Subtotal = $460,235

Issue Date FY: 2022 ( Subtotal = $539,989 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	008	4	7/13/2022	SUPPLEMENT FOR EXPANSION	$67,516
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	009	4	8/31/2022	SUPPLEMENT FOR EXPANSION	$128,939
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	007	4	7/12/2022	NON-COMPETING CONTINUATION	$343,534
2022	2021	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Alcohol Research Programs	005	1	2/16/2022	SUPPLEMENT FOR EXPANSION	-$69,281
2022	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Alcohol Research Programs	002	2	12/3/2021	SUPPLEMENT FOR EXPANSION	-$138,560
2022	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	003	3	12/3/2021	SUPPLEMENT FOR EXPANSION	$138,560
2022	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	001	3	11/9/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$351,687
2022	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Alcohol Research Programs	000	2	11/9/2021	NON-COMPETING CONTINUATION	-$351,687
2022	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	006	3	2/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$163,471
2022	2020	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Alcohol Research Programs	004	1	2/16/2022	NEW	-$94,190
														Subtotal = $539,989

Issue Date FY: 2021 ( Subtotal = $559,528 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Alcohol Research Programs	002	2	7/21/2021	NON-COMPETING CONTINUATION	$0
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Alcohol Research Programs	000	1	1/25/2021	SUPPLEMENT FOR EXPANSION	$69,281
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Alcohol Research Programs	001	2	6/29/2021	NON-COMPETING CONTINUATION	$351,687
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Alcohol Research Programs	003	2	8/17/2021	SUPPLEMENT FOR EXPANSION	$138,560
														Subtotal = $559,528

Issue Date FY: 2020 ( Subtotal = $373,452 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Alcohol Research Programs	000	1	8/27/2020	NEW	$373,452
														Subtotal = $373,452

Grand Total All Awards = $1,933,204

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Impact of chronic alcohol consumption on the functional and epigenetic landscapes of monocytes and their progenitors

Award Number: R01AA028735

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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