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Endoplasmic Reticulum Stress and Alcohol 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)
PERIOD OF PERFORMANCE START DATE: 08/01/2005
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Endoplasmic Reticulum Stress and Alcohol Neurotoxicity - Children who experience prenatal alcohol exposure may develop Fetal Alcohol Spectrum Disorders (FASD) and the central nervous system (CNS) is particularly susceptible to alcohol-induced damage. Children of FASD have significant neurobehavioral deficits. FASD is diagnosed at an alarmingly high rate making it the most common non-heritable cause of mental disability and resulting in tremendous personal and societal costs. It is therefore important to understand mechanisms that contribute to these adverse effects and find ways to improve outcomes in these individuals. The neurobehavioral deficits observed in FASD results from structural damages in the brain. It has been well-established that there is a temporal and spatial vulnerability to alcohol-induced neuronal damage during the development. That is, neurons at the different developmental stage display differential sensitivity to alcohol-induced damage. Even at the same developmental stage, neurons in different structures are differentially impacted by alcohol exposure. However, the underlying mechanisms are unclear. The endoplasmic reticulum (ER) is an important organelle involved in protein quality control. The accumulation of improperly folded proteins within the ER lumen results in ER stress, and sustained ER stress causes cell death. Neuronal cells are particularly sensitive to ER stress. Recently it is shown that ER stress plays an important and more specific role in alcohol-induced CNS damage. The ability of immature neurons to maintain ER homeostasis develops gradually and heterogeneously. We hypothesize that the temporal and spatial vulnerability of developing brain to alcohol-induced neuronal damage is mediated by the sensitivity to ER stress. That is, the differential sensitivity of neurons to alcohol neurotoxicity during the development is due to the difference of neuronal ability to maintain ER homeostasis and mitigate ER stress. We further hypothesize that enhancing neuronal ability to maintain ER homeostasis will make immature neurons resistant to alcohol-induced neurodegeneration and improve neurobehavioral deficits. We propose three specific aims to test these hypotheses. Specific Aim 1 will determine whether the temporal and spatial vulnerability to alcohol-induced neuronal damage is mediated by the sensitivity to ER stress in the developing brain. Specific Aim 2 will determine whether enhancing neuronal ability to maintain ER homeostasis can protect immature neurons against alcohol- induced ER stress and neurodegeneration in the developing brain. Specific Aim 3 will determine whether enhancing neuronal ability to maintain neuronal ER homeostasis can improve alcohol-induced neurobehavioral deficits. This proposal will use both in vitro and in vivo approaches to investigate how ER stress contributes to neuronal vulnerability to alcohol. It will employ genetic manipulations and chemical intervention by FDA-approved drugs to mitigate ER stress in immature neurons. The cohesive specific aims will not only elucidate the cellular and molecular mechanisms underlying the temporal and spatial vulnerability to alcohol, but also open a novel avenue for the intervention/therapy of FASD.


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: 2025 ( Subtotal = $380,182 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Alcohol Research Programs	000	20	5/1/2025	NON-COMPETING CONTINUATION	$380,182
														Subtotal = $380,182

Issue Date FY: 2024 ( Subtotal = $380,182 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Alcohol Research Programs	001	19	3/12/2024	NON-COMPETING CONTINUATION	$342,165
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Alcohol Research Programs	002	19	5/17/2024	NON-COMPETING CONTINUATION	$38,017
2024	2020	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Alcohol Research Programs	000	17	3/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $380,182

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
														Subtotal = $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
														Subtotal = $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 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	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	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
														Subtotal = $0

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
														Subtotal = $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
														Subtotal = $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
														Subtotal = $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	003	13	7/27/2017	NON-COMPETING CONTINUATION	$33,590
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	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
														Subtotal = $335,898

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
														Subtotal = $335,898

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
														Subtotal = $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
														Subtotal = $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
														Subtotal = $332,826

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
														Subtotal = $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
														Subtotal = $371,522

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	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
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	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
														Subtotal = $251,772

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
														Subtotal = $251,772

Issue Date FY: 2007 ( Subtotal = $251,772 ) (Continued on the next page)
Grand Total All Awards = $5,860,909

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Endoplasmic Reticulum Stress and Alcohol 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)

PERIOD OF PERFORMANCE START DATE: 08/01/2005

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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