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Involvement of TRP Channels in Ethanol Concentration-Dependent Effects on Immune

Award Number: R21AA023172
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: 09/28/2014
PERIOD OF PERFORMANCE END DATE: 08/31/2018

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Involvement of TRP Channels in Ethanol Concentration-Dependent Effects on Immune - DESCRIPTION (provided by applicant): Binge drinking, or the consumption of a large volume of alcoholic beverages in a very short time, is a serious social problem, particularly among adolescents and young adults. Ethanol (EtOH), the main ingredient in alcoholic beverages, is well known for its behavioral and psychological effects and also as an immune system modulator. However, the underlying mechanisms by which EtOH exerts its various effects are still not defined. Although recent evidence indicates that EtOH acts at the cellular level, there i still a fundamental gap between EtOH's potential cellular targets and its subsequent physiological effects. One such target is a group of cell membrane ion channels called transient receptor potential (TRP) channels. TRP channels are found in various cell types, including brain microvascular endothelial cells (BMVEC) of the blood-brain barrier (BBB). TRP channels mediate certain immune responses, such as cytokine production and leukocyte-endothelial adhesion (LEA), the initial step in the inflammatory process. Activation of TRP channels by various extracellular stimuli, including EtOH, induces an influx of calcium ions, which can subsequently increase LEA. Alcoholic beverages differ in their EtOH content or alcohol-by-volume (ABV) concentration, and EtOH's effects appear to be concentration dependent. We recently reported that binge consumption of solutions with high EtOH concentrations causes more pronounced immune responses than those with low EtOH concentrations, even when the amount of EtOH intake is the same. Based on the recent literature and our preliminary studies, we hypothesize that TRP channels mediate alcohol- induced immune responses at the blood-brain barrier (BBB) in an EtOH concentration- dependent manner. To test our hypothesis, we propose the following two specific aims: (1) To determine the effects of EtOH concentration on the structural binding of EtOH to TRPV4 channels in BMVEC using NMR spectroscopic techniques; and (2) To delineate the involvement of TRPV4 channels in the EtOH concentration-dependent effects on immune responses in the BMVEC at the BBB. In this application, we will combine investigation of the structural biology of EtOH-protein interactions with examination of EtOH's effects in animal and cell culture models to determine the mechanisms by which EtOH affects immune responses. This study is innovative because, to our knowledge, few studies have examined the relationship between EtOH-protein interaction and EtOH-induced immune effects at the level of the vascular endothelium. The NMR structural studies will provide essential details concerning EtOH-TRP binding and the EtOH concentration-dependent changes in target protein conformation. The molecular studies will then determine the correlation between those changes and the immunomodulatory effects of EtOH. Our study is highly significant and clinically relevant because it will provide valuable information on the mechanisms underlying the physiological effects of binge drinking with high ABV alcoholic beverages, which can help to prevent EtOH-induced dysregulation of immune responses and be used to develop therapeutic strategies to treat patients with alcoholic intoxication seen in the emergency room.


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: 2021 ( Subtotal = $0 )
2021	2015	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Alcohol Research Programs	001	2	10/3/2020	NON-COMPETING CONTINUATION	$2,000
2021	2015	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Alcohol Research Programs	000	2	10/1/2020	NON-COMPETING CONTINUATION	-$2,000
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = -$3,414 )
2020	2015	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Alcohol Research Programs	000	2	9/3/2020	NON-COMPETING CONTINUATION	-$3,414
														Subtotal = -$3,414

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2015	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Alcohol Research Programs	001	2	6/4/2018	NON-COMPETING CONTINUATION	$0
2018	2015	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Alcohol Research Programs	000	2	1/10/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Alcohol Research Programs	000	2	11/16/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $156,429 )
2015	2015	SETON HALL UNIVERSITY	400 SOUTH ORANGE AVENUE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Alcohol Research Programs	000	2	8/5/2015	NON-COMPETING CONTINUATION	$156,429
														Subtotal = $156,429

Issue Date FY: 2014 ( Subtotal = $196,560 )
2014	2014	SETON HALL UNIVERSITY	400 SOUTH ORANGE AVENUE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Alcohol Research Programs	000	1	9/28/2014	NEW	$196,560
														Subtotal = $196,560

Grand Total All Awards = $349,575

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Involvement of TRP Channels in Ethanol Concentration-Dependent Effects on Immune

Award Number: R21AA023172

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: 09/28/2014

PERIOD OF PERFORMANCE END DATE: 08/31/2018

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