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Ethanol actions on slo channels from arteries vs. brain.

Award Number: R01AA011560
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: 01/01/1999
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Ethanol actions on slo channels from arteries vs. brain. - Alcohol-induced blackouts (AIB), a form of amnesia linked to dysfunction of the hippocampal CA1 region, often occur upon moderate-heavy, acute ethanol consumption disregarding age, drinking history, biological sex, gender or education. Despite their high prevalence and detrimental impact on individuals, families and society, biomedical research has largely failed to identify the molecular targets underlying AIB and, more important, to develop pharmacotherapeutic approaches to counteract them. We will cover these gaps in knowledge by departing from all previous work, which focused on AIB-induced disruption of mechanisms operating at the hippocampal neurons themselves, to advance a vascular theory of AIB that is centered on the β1 subunit of ion channels of BK type that is highly expressed in cerebrovascular smooth muscle. Thus, we will test this overarching hypothesis: at concentrations reached in the brain during AIB, specific amino acids (e.g., S160) in BK β1 mediate alcohol-induced BK channel inhibition and, eventually, cerebral artery constriction thus leading to AIB, all these actions being counteracted by selective, novel β1 transmembrane region 2 (TM2)-targeting agents that activate BK channels. We will address three conceptually related, yet independently testable specific aims (SA): SA1 (molecular-cellular resolution) will identify the central role of β1 S160 in mediating ethanol inhibition of BK channels and its reversion by novel β1 TM2-targeting agents whether drug actions are studied using recombinant BK proteins expressed in heterologous, isolated membranes or in the native cell. SA2 (tissue-organ resolution) will identify the role of β1 TM2 specific amino acids in ethanol actions of middle cerebral artery constriction, both in vitro and in vivo, and the reversion of ethanol actions by the β1 TM2- targeting agents. SA3 (organismal resolution) will address the impact of β1 TM2 specific amino acids in a mouse model of AIB and demonstrate AIB reversion by β1 TM2-targeting agents. Testing of the three SAs will be accomplished by combining computational modeling, nano differential scanning fluorimetry (nanoDSF), point mutagenesis, robotic/manual patch-clamp, electroporation of vascular myocytes and middle cerebral artery with recombinant DNAs, engineered mice (“knockouts” and “knockins”), middle cerebral artery in vitro and in vivo (cranial window) diameter determinations, selective pharmacology, and simultaneous evaluation of CA1 vessels, blood flow and neuron activity in freely behaving mice subject to AIB, all supported by our papers or preliminary data.


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 = $538,205 )
2025	2025	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	25	9/10/2025	NON-COMPETING CONTINUATION	$538,205
														Subtotal = $538,205

Issue Date FY: 2024 ( Subtotal = $538,205 )
2024	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	24	7/31/2024	NON-COMPETING CONTINUATION	$538,205
														Subtotal = $538,205

Issue Date FY: 2023 ( Subtotal = $573,305 )
2023	2023	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	002	23	9/9/2023	NON-COMPETING CONTINUATION	$0
2023	2023	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	001	23	8/24/2023	NON-COMPETING CONTINUATION	$549,666
2023	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	22	12/29/2022	COMPETING CONTINUATION	$23,639
														Subtotal = $573,305

Issue Date FY: 2022 ( Subtotal = $507,693 )
2022	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	22	9/9/2022	COMPETING CONTINUATION	$507,693
														Subtotal = $507,693

Issue Date FY: 2009 ( Subtotal = $353,276 )
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	001	12	7/7/2009	COMPETING CONTINUATION	$353,276
2009	2008	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	11	7/7/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $353,276

Issue Date FY: 2008 ( Subtotal = $280,102 )
2008	2008	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	11	3/14/2008	NON-COMPETING CONTINUATION	$280,102
														Subtotal = $280,102

Issue Date FY: 2007 ( Subtotal = $277,098 )
2007	2007	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	10	3/22/2007	NON-COMPETING CONTINUATION	$277,098
														Subtotal = $277,098

Issue Date FY: 2006 ( Subtotal = $288,508 )
2006	2006	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	9	3/23/2006	NON-COMPETING CONTINUATION	$288,508
														Subtotal = $288,508

Issue Date FY: 2005 ( Subtotal = $290,940 )
2005	2005	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	8	3/8/2005	NON-COMPETING CONTINUATION	$290,940
														Subtotal = $290,940

Issue Date FY: 2004 ( Subtotal = $256,033 )
2004	2004	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	7	4/30/2004	COMPETING CONTINUATION	$256,033
														Subtotal = $256,033

Issue Date FY: 2003 ( Subtotal = $119,097 )
2003	2003	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	6		NON-COMPETING CONTINUATION	$119,097
														Subtotal = $119,097

Issue Date FY: 2002 ( Subtotal = $114,014 )
2002	2002	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	5	12/31/2001	NON-COMPETING CONTINUATION	$114,014
														Subtotal = $114,014

Issue Date FY: 2001 ( Subtotal = $111,147 )
2001	2001	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Alcohol Research Programs	000	4	8/16/2001	NON-COMPETING CONTINUATION	$111,147
														Subtotal = $111,147

Grand Total All Awards = $4,247,623

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Ethanol actions on slo channels from arteries vs. brain.

Award Number: R01AA011560

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: 01/01/1999

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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