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Regulation of GABAA Receptors by PKCe

Award Number: R01AA013588
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: 05/01/2002
PERIOD OF PERFORMANCE END DATE: 07/31/2018

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Regulation of GABAA Receptors by PKCe - DESCRIPTION (provided by applicant): Alcohol use disorders are common and incur a huge cost to society. Unfortunately, pharmacotherapy of alcohol use disorders is restricted to three FDA approved drugs: disulfuram, naltrexone, and acamprosate. Therefore, there is considerable need for the development of new agents to treat these disorders. Mounting evidence suggests that protein kinase C epsilon (PKC¿) is a good target for development of drugs to treat alcohol use disorders, based mainly on studies using gene-targeted mice that lack this enzyme (Prkce-/- mice). These mice drink substantially less ethanol than wild type mice, show heightened aversion to ethanol, are more easily intoxicated by low doses of ethanol, and recover from intoxication very slowly compared with wild type mice. These behaviors are associated with enhanced function of GABAA receptors, which are the major mediators of inhibitory neurotransmission in the nervous system. PKC¿ regulates GABAA receptors by phosphorylating GABAA ¿2 subunits at Ser-327, which reduces their sensitivity to benzodiazepines and ethanol. PKC¿ also phosphorylates the N-ethylmaleimide sensitive factor (NSF), at Ser-460 and Thr-461, which stimulates removal of GABAA receptors from synapses. The long-term goal of this project is to identify targets for the development of new drugs to treat alcohol use disorders. The objective of this application is to specifically validate PKC¿ as a drug target and identify additional drug targets within neuronal PKC¿ signaling pathways. The main hypothesis to be tested is that selective inhibitors of PKC¿ signaling can reduce voluntary ethanol consumption in mice. Three aims are proposed. The first aim will determine the consequences of administering a highly selective PKC¿ inhibitor and validate PKC¿ as a drug target to decrease alcohol consumption. This will be achieved by using a new line of mutant mice in which the ATP binding pocket of PKC¿ has been modified to allow highly specific inhibition by small molecules that do not inhibit native kinases. In the second aim, three novel, related compounds that are potent inhibitors of PKC¿ will be administered to wild type mice to determine if this class of compounds should be developed further as drugs to treat alcohol use disorders. The third aim will use a newly developed proteomics approach to identify direct substrates of PKC¿ for study of their role in regulating GABAA receptors and behavioral responses to ethanol. Because of its focus on identifying new drug targets and pharmacological agents to treat alcohol use disorders, this project has high translational value for serving public health.


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: 2019 ( Subtotal = -$588 )
2019	2016	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	002	16	2/21/2019	EXTENSION WITH OR WITHOUT FUNDS	$434
2019	2016	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	003	16	5/8/2019	EXTENSION WITH OR WITHOUT FUNDS	-$434
2019	2016	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	16	12/20/2018	EXTENSION WITH OR WITHOUT FUNDS	-$154
2019	2015	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	001	15	2/21/2019	NON-COMPETING CONTINUATION	-$434
														Subtotal = -$588

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	001	16	2/3/2017	EXTENSION WITH OR WITHOUT FUNDS	$35,605
2017	2015	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Alcohol Research Programs	000	15	2/3/2017	NON-COMPETING CONTINUATION	-$35,605
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $308,155 )
2016	2016	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	16	7/19/2016	EXTENSION WITH OR WITHOUT FUNDS	$308,155
														Subtotal = $308,155

Issue Date FY: 2015 ( Subtotal = $239,329 )
2015	2015	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	001	15	7/14/2015	NON-COMPETING CONTINUATION	$269,488
2015	2014	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	14	3/11/2015	NON-COMPETING CONTINUATION	-$30,159
														Subtotal = $239,329

Issue Date FY: 2014 ( Subtotal = $329,045 )
2014	2014	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	14	7/9/2014	NON-COMPETING CONTINUATION	$329,045
														Subtotal = $329,045

Issue Date FY: 2013 ( Subtotal = $315,962 )
2013	2013	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	002	13	9/9/2013	NON-COMPETING CONTINUATION	$315,962
2013	2012	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Alcohol Research Programs	001	11	8/27/2013	COMPETING CONTINUATION	-$238,101
2013	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	12	8/27/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$238,101
														Subtotal = $315,962

Issue Date FY: 2012 ( Subtotal = $354,397 )
2012	2012	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Alcohol Research Programs	000	11	7/27/2012	COMPETING CONTINUATION	$354,397
														Subtotal = $354,397

Issue Date FY: 2002 ( Subtotal = $401,750 )
2002	2002	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Alcohol Research Programs	000	1	4/23/2002	NEW	$401,750
														Subtotal = $401,750

Grand Total All Awards = $1,948,050

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Regulation of GABAA Receptors by PKCe

Award Number: R01AA013588

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: 05/01/2002

PERIOD OF PERFORMANCE END DATE: 07/31/2018

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