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PKC DELTA IN ETHANOL REGULATION OF GABA-A RECEPTORS AND BEHAVIOR

Award Number: R01AA018316
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: 09/20/2009
PERIOD OF PERFORMANCE END DATE: 06/30/2015

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PKC DELTA IN ETHANOL REGULATION OF GABA-A RECEPTORS AND BEHAVIOR - DESCRIPTION (provided by applicant): Studies with protein kinase C delta knockout (PKC4-/-) mice indicate that PKC4 regulates ethanol intoxication and self-administration. These effects may be related to PKC4 actions at extrasynaptic GABAA receptors, since thalamic and hippocampal neurons from PKC4-/- mice lack ethanol enhancement of tonic inhibitory GABA currents. The main hypothesis of this project is that PKC4 regulates ethanol intoxication and self-administration by phosphorylating proteins that alter the function of extrasynaptic GABAA receptors in brain regions controlling these behaviors. This hypothesis will be tested using a novel mouse model, a knock-in mouse that expresses an ATP analog-sensitive mutant of PKC4 (AS-PKC4). AS-PKC4 can be selectively and potently inhibited by analogs of the general kinase inhibitor PP1 that cross the blood brain barrier and can be administered orally or by i.p. injection. Studies will determine if inhibition of AS-PKC4 mice increases signs of ethanol intoxication and enhances ethanol self-administration in adult mice. Electrophysiological studies in brain slices will investigate whether inhibiting AS-PKC4 blocks ethanol potentiation of tonic GABA currents in hippocampal, thalamic, and amygdala neurons. In vitro kinase assays will determine if 22, 23, and 4 subunits are possible substrates of PKC4. Novel ATP analogs will be used with tissues from AS-PKC4 mice to identify PKC4 phosphorylation sites on GABAA receptor-associated proteins. Studies in cells that heterologously express 1422/34 receptors and receptor-associated proteins with alanine substitutions at PKC4 phosphorylation sites, will determine if these sites regulate the ethanol sensitivity of 1422/34 receptors. The overall goal of this project is to identify a novel PKC4 signaling pathway that regulates the ethanol sensitivity of extrasynaptic GABAA receptors and may contain targets for the development of new therapeutics to treat alcohol use disorders. PUBLIC HEALTH RELEVANCE We will investigate the role of PKC4 in ethanol's effects on behavior and on regulation of GABAA receptors. These studies will utilize an ATP-analog sensitive form of PKC4 that can be inhibited with high selectivity and specificity, and can be used to identify PKC4 substrates. The results of these studies will reveal new molecular mechanisms that regulate GABA signaling, behavioral sensitivity to ethanol, and ethanol consumption.


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: 2013 ( Subtotal = $278,307 )
2013	2013	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	003	6	8/27/2013	NON-COMPETING CONTINUATION	$18,392
2013	2013	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	002	6	6/21/2013	NON-COMPETING CONTINUATION	$272,921
2013	2012	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Alcohol Research Programs	001	4	5/22/2013	NON-COMPETING CONTINUATION	-$286,036
2013	2012	UNIVERSITY OF TEXAS AT AUSTIN	P.O. BOX 7159	AUSTIN	TX	78713	TRAVIS	USA	Alcohol Research Programs	000	5	5/22/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$273,030
														Subtotal = $278,307

Issue Date FY: 2012 ( Subtotal = $336,382 )
2012	2012	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Alcohol Research Programs	000	4	6/20/2012	NON-COMPETING CONTINUATION	$336,382
														Subtotal = $336,382

Issue Date FY: 2011 ( Subtotal = $336,382 )
2011	2011	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Alcohol Research Programs	000	3	7/8/2011	NON-COMPETING CONTINUATION	$336,382
														Subtotal = $336,382

Issue Date FY: 2010 ( Subtotal = $349,960 )
2010	2010	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Alcohol Research Programs	000	2	6/23/2010	NON-COMPETING CONTINUATION	$349,960
														Subtotal = $349,960

Issue Date FY: 2009 ( Subtotal = $377,245 )
2009	2009	ERNEST GALLO CLINIC & RESEARCH CENTER	5858 HORTON STREET, SUITE 200	EMERYVILLE	CA	94608	ALAMEDA	USA	Alcohol Research Programs	000	1	9/16/2009	NEW	$377,245
														Subtotal = $377,245

Grand Total All Awards = $1,678,276

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PKC DELTA IN ETHANOL REGULATION OF GABA-A RECEPTORS AND BEHAVIOR

Award Number: R01AA018316

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: 09/20/2009

PERIOD OF PERFORMANCE END DATE: 06/30/2015

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