Monday, October 2, 2023 10/2/2023

GSK3BETA, A MEDIATOR OF ETHANOL NEUROTOXICITY

Award Number: R01AA015407
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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View Award Abstract

Ethanol is a neuroteratogen and alcohol consumption during pregnancy causes Fetal Alcohol Spectrum Disorders (FASD). FASD are currently the leading cause of mental retardation in North America. The most devastating effect of developmental exposure to ethanol is the loss of CNS neurons which underlie many behavioral deficits observed in FASD. We demonstrated that ethanol caused both oxidative stress and endoplasmic reticulum (ER) stress in the developing brain. We showed that ethanol induced the expression of monocyte chemoattractant protein-1 (MCP-1) and a specific ER stress-inducible protein, mesencephalic astrocyte-derived neurotrophic factor (MANF). Our studies suggested that both MCP-1 and MANF were involved in ethanol-induced ER stress and neuron death. The central hypothesis for this proposal is that ethanol-induced neurodegeneration in the developing brain is mediated by the interplay of oxidative stress and ER stress. Three corollary hypotheses will be tested: 1) ethanol-mediated oxidative stress causes an early neuron death; the second phase of neuron death is mainly mediated by ethanol-induced ER stress or a combined action of both oxidative stress and ER stress; 2) the oxidative stress-induced neuron death is mainly regulated by the mitochondrial intrinsic apoptotic pathway; while the ER stress-induced neuron death is mediated by the GSK3ß/calpain/caspase7/12 pathway; 3) activation of MCP-1 mediated signaling potentiates ethanol-induced ER stress and promotes an ER stress-initiated apoptotic program in neurons; contrarily, MANF is a neuroprotective protein which alleviates ethanol-induced ER stress and neuron death. We propose three specific aims to test these hypotheses. Specific Aim 1 will test the hypothesis that ethanol-induced neuron death is caused by the interplay of oxidative stress and ER stress in vitro. Specific Aim 2 will determine the role of MCP-1 signaling and MANF in ethanol-induced ER stress and neuron death in the developing brain. Specific Aim 3 will determine whether simultaneous inhibition of oxidative stress and ER stress offers maximal protection and improves behavioral deficits in mice. As a unit, this proposal will systematically investigate the interplay of oxidative stress and ER stress and assess their contribution to ethanol-induced neuron death. This study will therefore not only provide novel insight into the mechanisms of ethanol-induced damage to the developing CNS but also identify specific targets for developing effective therapeutic strategies.


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 = $380,182 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Alcohol Research Programs	000	18	3/3/2023	COMPETING CONTINUATION	$380,182


Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Alcohol Research Programs	000	17	3/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0


Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Alcohol Research Programs	001	17	11/25/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$338,011
2021	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Alcohol Research Programs	003	17	1/29/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$69,883
2021	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	000	16	11/25/2020	NON-COMPETING CONTINUATION	-$338,011
2021	2019	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	002	15	1/29/2021	NON-COMPETING CONTINUATION	-$69,883


Issue Date FY: 2020 ( Subtotal = $338,011 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	000	16	4/20/2020	NON-COMPETING CONTINUATION	$338,011


Issue Date FY: 2019 ( Subtotal = $338,011 )
2019	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	000	15	4/12/2019	NON-COMPETING CONTINUATION	$338,011


Issue Date FY: 2018 ( Subtotal = $335,898 )
2018	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	000	14	4/26/2018	NON-COMPETING CONTINUATION	$335,898


Issue Date FY: 2017 ( Subtotal = $335,898 )
2017	2017	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	002	13	4/10/2017	NON-COMPETING CONTINUATION	$302,308
2017	2017	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	003	13	7/27/2017	NON-COMPETING CONTINUATION	$33,590
2017	2016	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	001	12	12/2/2016	COMPETING CONTINUATION	$119,439
2017	2015	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Alcohol Research Programs	000	11	12/2/2016	NON-COMPETING CONTINUATION	-$119,439


Issue Date FY: 2016 ( Subtotal = $335,898 )
2016	2016	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	001	12	8/8/2016	COMPETING CONTINUATION	$335,898
2016	2015	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	000	11	7/29/2016	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2015 ( Subtotal = $347,141 )
2015	2015	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	000	11	2/16/2015	NON-COMPETING CONTINUATION	$347,141


Issue Date FY: 2014 ( Subtotal = $347,141 )
2014	2014	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	000	10	2/26/2014	NON-COMPETING CONTINUATION	$347,141


Issue Date FY: 2013 ( Subtotal = $332,826 )
2013	2013	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	001	9	5/22/2013	NON-COMPETING CONTINUATION	$10,738
2013	2013	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	000	9	2/11/2013	NON-COMPETING CONTINUATION	$322,088


Issue Date FY: 2012 ( Subtotal = $357,878 )
2012	2012	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	000	8	2/17/2012	NON-COMPETING CONTINUATION	$357,878


Issue Date FY: 2011 ( Subtotal = $371,522 )
2011	2011	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	001	7	3/7/2011	COMPETING CONTINUATION	$371,522
2011	2009	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	109 KINEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	000	6	3/3/2011	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2009 ( Subtotal = $251,772 )
2009	2009	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	109 KINEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	004	6	7/22/2009	NON-COMPETING CONTINUATION	$251,772
2009	2008	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	109 KINEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	002	5	1/12/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$149,421
2009	2008	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	109 KINEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Alcohol Research Programs	003	5	2/16/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$77,812
2009	2008	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	POB 6001, UNIV SVCS CTR #3038B	MORGANTOWN	WV	26506	MONONGALIA	USA	Alcohol Research Programs	000	4	1/12/2009	NON-COMPETING CONTINUATION	-$149,421
2009	2008	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	POB 6001, UNIV SVCS CTR #3038B	MORGANTOWN	WV	26506	MONONGALIA	USA	Alcohol Research Programs	001	4	2/16/2009	NON-COMPETING CONTINUATION	-$77,812


Issue Date FY: 2008 ( Subtotal = $251,772 )
2008	2008	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	POB 6001, UNIV SVCS CTR #3038B	MORGANTOWN	WV	26506	MONONGALIA	USA	Alcohol Research Programs	000	4	7/22/2008	NON-COMPETING CONTINUATION	$251,772


Issue Date FY: 2007 ( Subtotal = $251,772 )
2007	2007	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	POB 6001, UNIV SVCS CTR #3038B	MORGANTOWN	WV	26506	MONONGALIA	USA	Alcohol Research Programs	000	3	7/23/2007	NON-COMPETING CONTINUATION	$251,772


Issue Date FY: 2006 ( Subtotal = $259,292 )
2006	2006	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	POB 6001, UNIV SVCS CTR #3038B	MORGANTOWN	WV	26506	MONONGALIA	USA	Alcohol Research Programs	000	2	7/27/2006	NON-COMPETING CONTINUATION	$259,292


Issue Date FY: 2005 ( Subtotal = $265,531 )
2005	2005	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	POB 6001, UNIV SVCS CTR #3038B	MORGANTOWN	WV	26506	MONONGALIA	USA	Alcohol Research Programs	000	1	7/22/2005	NEW	$265,531


Grand Total All Awards = $5,100,545

Sum of Action Amount is $5,100,545;

Grand Total = $5,100,545

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GSK3BETA, A MEDIATOR OF ETHANOL NEUROTOXICITY

Award Number: R01AA015407

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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