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7/11 Biochemical and Genetic Determinants of Alcohol Consumption

Award Number: U01AA013520
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/27/2001
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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7/11 Biochemical and Genetic Determinants of Alcohol Consumption - PROJECT SUMMARY This project is a continuation and further development of a previous INIA project, which was based on studies showing ethanol-induced changes in neuroimmune gene expression in animal models and humans. Those data suggested that ethanol dysregulates Toll-like receptor (TLR) signaling through the myeloid differentiation primary response gene 88 (MyD88) and thereby promotes excessive ethanol intake. Our most recent work showed that genetic and pharmacological manipulation of another branch of TLR signaling via the TIR-domain- containing adapter-inducing interferon-β (TRIF) protein also regulates ethanol intake. In exploring downstream mechanisms by which these signaling disruptions act, we found that chronic alcohol consumption increased several TRIF-dependent signaling components, including type 1 interferons (IFN1s). These findings lead us to the central hypothesis of this renewal application, which is that chronic alcohol exposure activates pathways leading to IFN1 production and expression of interferon-stimulated genes (ISGs), which increase alcohol consumption. To test this hypothesis, we will study alcohol intake and alcohol-related behaviors in mice deficient in critical components of pathways leading to IFN1 production and signaling, and in mice administered compounds that block IFN1 signaling. The proposal has three Specific Aims. Specific Aim 1 will study changes in alcohol consumption in mice undergoing every other day two-bottle choice (EOD-2BC) drinking for at least 4 weeks. To reduce IFN1 production, we will examine these behaviors in mice with genetic deletion of the transcription factors Irf3 or Irf7. To examine the role of IFN1 signaling, we will use Ifnar1 knockout mice which carry a null mutation in the IFN1 receptor. We will also study wild-type mice treated with inhibitors of the kinase TYK2, which mediates IFN1 receptor signaling. Specific Aim 2 will determine if EOD-2BC drinking induces IFN1 responses in specific brain regions by detecting Fos expression in Mx1GFP mice in which the interferon-stimulated response element of the Mx1 gene drives GFP expression. Data from these whole brain imaging studies will be shared with the Harsan-Keiffer project to be incorporated into their multimodal connectome analyses. To determine if IFN1 regulates alcohol responses in certain regions, we will knockout Ifnar1 using local microinjection of Cre recombinase in floxed Ifnar mice and use Fos-Cre-ER (TRAP2) mice to knockout or knockdown Ifnar1 in activated neurons and glia. Specific Aim 3 will identify ISGs induced by EOD-2BC alcohol drinking in brain regions identified in Aim 2. The Mayfield project will help us analyze transcriptomic data to identify ISGs. To investigate causality, groups of ISGs will be knocked down using multiplex CRISPR interference in collaboration with the Farris-Homanics project. We anticipate that some other INIA projects will identify additional proteins that require behavioral testing with pharmacological agents or genetically modified mice, which we will carry out as part of this consortium. !


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 = $454,375 )
2026	2026	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	25	2/6/2026	NON-COMPETING CONTINUATION	$454,375
														Subtotal = $454,375

Issue Date FY: 2025 ( Subtotal = $454,375 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	24	3/4/2025	NON-COMPETING CONTINUATION	$408,938
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	001	24	8/12/2025	NON-COMPETING CONTINUATION	$45,437
														Subtotal = $454,375

Issue Date FY: 2024 ( Subtotal = $454,375 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	23	1/30/2024	NON-COMPETING CONTINUATION	$408,938
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	001	23	5/21/2024	NON-COMPETING CONTINUATION	$45,437
														Subtotal = $454,375

Issue Date FY: 2023 ( Subtotal = $454,375 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	22	1/30/2023	NON-COMPETING CONTINUATION	$454,375
														Subtotal = $454,375

Issue Date FY: 2022 ( Subtotal = $479,439 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	001	21	3/22/2022	COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	003	21	7/11/2022	COMPETING CONTINUATION	$14,105
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	21	2/22/2022	COMPETING CONTINUATION	$479,439
2022	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	002	20	7/11/2022	NON-COMPETING CONTINUATION	-$14,105
														Subtotal = $479,439

Issue Date FY: 2021 ( Subtotal = $452,925 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	20	1/15/2021	NON-COMPETING CONTINUATION	$452,925
														Subtotal = $452,925

Issue Date FY: 2020 ( Subtotal = $452,925 )
2020	2020	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	19	1/22/2020	NON-COMPETING CONTINUATION	$452,925
														Subtotal = $452,925

Issue Date FY: 2019 ( Subtotal = $452,925 )
2019	2019	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	18	1/24/2019	NON-COMPETING CONTINUATION	$452,925
														Subtotal = $452,925

Issue Date FY: 2018 ( Subtotal = $452,925 )
2018	2018	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	004	17	8/23/2018	NON-COMPETING CONTINUATION	$0
2018	2018	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	17	1/29/2018	NON-COMPETING CONTINUATION	$407,632
2018	2018	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	003	17	5/23/2018	NON-COMPETING CONTINUATION	$45,293
2018	2017	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	001	16	2/22/2018	COMPETING CONTINUATION	$11,159
2018	2016	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	002	15	2/22/2018	SUPPLEMENT FOR EXPANSION	-$11,159
														Subtotal = $452,925

Issue Date FY: 2017 ( Subtotal = $452,925 )
2017	2017	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	004	16	8/18/2017	COMPETING CONTINUATION	$452,925
2017	2017	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	003	16	8/2/2017	COMPETING CONTINUATION	-$452,925
2017	2017	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	16	2/1/2017	COMPETING CONTINUATION	$452,925
2017	2017	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	002	16	6/7/2017	COMPETING CONTINUATION	$10,083
2017	2015	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	001	15	6/7/2017	NON-COMPETING CONTINUATION	-$10,083
														Subtotal = $452,925

Issue Date FY: 2016 ( Subtotal = $177,600 )
2016	2016	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	15	8/26/2016	SUPPLEMENT FOR EXPANSION	$177,600
2016	2015	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	001	15	8/26/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $177,600

Issue Date FY: 2015 ( Subtotal = $426,241 )
2015	2015	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	15	8/5/2015	NON-COMPETING CONTINUATION	$426,241
														Subtotal = $426,241

Issue Date FY: 2014 ( Subtotal = $439,573 )
2014	2014	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	13	4/30/2014	SUPPLEMENT FOR EXPANSION	$13,332
2014	2014	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	001	14	8/4/2014	NON-COMPETING CONTINUATION	$426,241
														Subtotal = $439,573

Issue Date FY: 2013 ( Subtotal = $371,464 )
2013	2013	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	13	8/7/2013	NON-COMPETING CONTINUATION	$371,464
														Subtotal = $371,464

Issue Date FY: 2012 ( Subtotal = $398,132 )
2012	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	12	7/27/2012	NON-COMPETING CONTINUATION	$398,132
														Subtotal = $398,132

Issue Date FY: 2011 ( Subtotal = $398,132 )
2011	2011	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	11	9/5/2011	COMPETING CONTINUATION	$398,132
														Subtotal = $398,132

Issue Date FY: 2010 ( Subtotal = $202,866 )
2010	2010	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	10	9/1/2010	NON-COMPETING CONTINUATION	$202,866
														Subtotal = $202,866

Issue Date FY: 2009 ( Subtotal = $198,945 ) (Continued on the next page)
Grand Total All Awards = $9,139,363

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7/11 Biochemical and Genetic Determinants of Alcohol Consumption

Award Number: U01AA013520

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/27/2001

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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