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Identifying new targets for the treatment of alcohol dependence and relapse: epigenetic analysis of the abstinent brain

Award Number: R01AA027552
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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SUMMARY Alcohol use disorder (AUD) affects more than 12% of the US population and is the fourth leading preventable cause of death in the US. AUD is associated with compulsive drinking and emergence of a negative emotional state during abstinence, resulting in two-thirds of afflicted people relapsing within months of completing alcohol cessation treatment. Repeated cycles of intoxication and abstinence are linked to persistent alterations in the brain that remain long after detoxification, which drive relapse of drinking, often at levels higher than before abstinence. Identifying the molecular mechanisms that lead to hazardous alcohol use and contribute to the high rates of relapse is imperative for the effective design of better treatments to curb alcohol abuse. Our previous studies illustrate the power of integrating epigenetic, transcriptomic, circuitry, pharmacology and behavioral tools to elucidate the molecular underpinnings contributing to hazardous alcohol use. Those studies, using genome- wide DNA methylation (DNAm) analysis of the nucleus accumbens (NAc) to compare macaque alcohol-naive and alcohol-drinkers, identified differential DNAm (D-DNAm) signals, mapping to genes not previously linked to alcohol use, but with high relevance to synaptic plasticity modulation. Experimental manipulation of two of these DNAm-linked genes resulted in altered glutamate and GABA neurotransmission and changes in ethanol intake. The the next critical step is to understand how repeated abstinence/relapse cycles alters DNAm signals and how these changes contribute to adaptations in neurocircuitry. We hypothesize that some D-DNAm signals associated with chronic alcohol use may persist during abstinence, contributing to risk of relapse. In addition, de novo D-DNAm signals generated during repeated cycles of abstinence/relapse, may further heighten relapse risk. To identify abstinence-associated DNAm, we will use the highly translational macaque alcohol self- administration model and our proven genome-wide approach to identify D-DNAm in the NAc of macaques following > 12 months of chronic alcohol self-administration and then 3 cycles of forced abstinence (each cycle: 1 month abstinence and 3 months of open-access). After integrating gene and transcript variant expression and D-DNAm data generated from the same subjects and tissues, a subset of compelling, novel targets will be selected for functional study using pharmacological and genetic manipulation approaches in a mouse chronic intermittent ethanol (CIE) model. This rodent CIE model has been extensively used to model cycles of alcohol exposure and withdrawal leading to an escalation of drinking during relapse. In addition to recording ethanol intake, the effects of target manipulation on neurotransmission will be evaluated using patch-clamp electrophysiological analysis. Overall, these studies will aid in our understanding of the molecular mechanism(s) establishing risk for relapse. This information will be critical to advancing the development of effective therapies for alcohol abuse and to prevent relapse.


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 = $413,492 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	5	5/10/2024	NON-COMPETING CONTINUATION	$413,492
														Subtotal = $413,492

Issue Date FY: 2023 ( Subtotal = $441,358 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	4	5/10/2023	NON-COMPETING CONTINUATION	$441,358
														Subtotal = $441,358

Issue Date FY: 2022 ( Subtotal = $425,509 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	005	3	9/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$425,509
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	3	6/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$425,509
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	003	3	7/20/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$400,936
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	004	3	9/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$425,509
2022	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	2	6/20/2022	NON-COMPETING CONTINUATION	$0
2022	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	002	2	7/20/2022	NON-COMPETING CONTINUATION	-$400,936
														Subtotal = $425,509

Issue Date FY: 2021 ( Subtotal = $671,508 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	2	4/22/2021	NON-COMPETING CONTINUATION	$671,508
														Subtotal = $671,508

Issue Date FY: 2020 ( Subtotal = $691,939 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	1	7/30/2020	NEW	$691,939
														Subtotal = $691,939

Grand Total All Awards = $2,643,806

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Identifying new targets for the treatment of alcohol dependence and relapse: epigenetic analysis of the abstinent brain

Award Number: R01AA027552

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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