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Effects of Ethanol TNF Induced Cytotoxicity

Award Number: R01AA012897
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: 12/01/2000
PERIOD OF PERFORMANCE END DATE: 02/29/2016

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Effects of Ethanol TNF Induced Cytotoxicity - DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) constitutes a spectrum of disorders in liver structure and function. The alterations in ALD are broadly categorized into alcohol induced steatosis, steatohepatitis and cirrhosis. Tumor necrosis factor (TNF) has been shown to play a critical role in the progression of ALD, partly through it ability to bring about the injury and death of hepatocytes. In the preceding period of support we have uncovered that hepatocytes exposed to ethanol display an increased sensitivity to TNF induced cytotoxicity and that this is driven by an enhanced susceptibility of the mitochondria to injury, which in turn is exploited by alterations in signaling pathways elicited by TNF in ethanol exposed cells. In the present application we intend to both narrow and broaden the scope of our studies. Firstly, we propose that modifications to hepatocyte lipogenesis contribute to the increased vulnerability to TNF induced damage that characterizes the mitochondria of ethanol exposed cells. Specifically, increased expression of acyl CoA binding protein (ACBP) and the peripheral benzodiazepine receptor (PBR) in ethanol exposed cells, proteins involved in lipid and cholesterol metabolism, establish an enhanced susceptibility of the mitochondria to TNF induced damage. Also, derangements of the PI3-kinase/Akt pathway brought about by ethanol exposure results in phosphorylation of the voltage dependent anion carrier (VDAC), with detrimental consequences for mitochondrial function and resistance to injury. The preliminary data also reveal that the alterations imposed on mitochondria by ethanol exposure may mitigate the beneficial effects of adiponectin against TNF induced cytotoxicity, potentially by impeding adiponectin induced activation of the AMPK pathway. The working hypothesis for this proposal is that the derangement of lipogenesis triggered by ethanol exposure causes alterations in mitochondrial function, particularly through an increased expression of acyl CoA binding protein, the peripheral benzodiazepine receptor, phosphorylation of the voltage dependent anion carrier (VDAC) and endoplasmic reticulum stress, all of which render the mitochondria and cell more sensitive to TNF induced injury. Moreover these effects of ethanol can be ameliorated by activation of AMPK.


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: 2015 ( Subtotal = $0 )
2015	2012	ROWAN UNIVERSITY	201 MULLICA HILL ROAD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Alcohol Research Programs	000	12	7/10/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Alcohol Research Programs	000	11	2/11/2014	NON-COMPETING CONTINUATION	$0
2014	2012	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Alcohol Research Programs	002	11	3/10/2014	NON-COMPETING CONTINUATION	-$246,795
2014	2012	ROWAN UNIVERSITY	201 MULLICA HILL ROAD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Alcohol Research Programs	001	12	3/10/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$246,795
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $246,795 )
2012	2012	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Alcohol Research Programs	000	11	2/29/2012	NON-COMPETING CONTINUATION	$246,795
														Subtotal = $246,795

Issue Date FY: 2011 ( Subtotal = $246,795 )
2011	2011	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Alcohol Research Programs	001	10	6/27/2011	NON-COMPETING CONTINUATION	$15,714
2011	2011	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Alcohol Research Programs	000	10	2/17/2011	NON-COMPETING CONTINUATION	$231,081
														Subtotal = $246,795

Issue Date FY: 2010 ( Subtotal = $256,757 )
2010	2010	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Alcohol Research Programs	000	9	2/19/2010	NON-COMPETING CONTINUATION	$256,757
														Subtotal = $256,757

Issue Date FY: 2009 ( Subtotal = $259,350 )
2009	2009	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Alcohol Research Programs	000	8	2/18/2009	NON-COMPETING CONTINUATION	$233,415
2009	2009	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Alcohol Research Programs	001	8	5/5/2009	NON-COMPETING CONTINUATION	$25,935
														Subtotal = $259,350

Issue Date FY: 2008 ( Subtotal = $259,350 )
2008	2008	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Alcohol Research Programs	000	7	2/25/2008	COMPETING CONTINUATION	$259,350
														Subtotal = $259,350

Issue Date FY: 2006 ( Subtotal = $229,966 )
2006	2006	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Alcohol Research Programs	000	5	6/20/2006	NON-COMPETING CONTINUATION	$229,966
														Subtotal = $229,966

Issue Date FY: 2005 ( Subtotal = $183,167 )
2005	2005	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Alcohol Research Programs	000	4	6/17/2005	NON-COMPETING CONTINUATION	$183,167
														Subtotal = $183,167

Issue Date FY: 2004 ( Subtotal = $183,167 )
2004	2004	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Alcohol Research Programs	000	3	6/17/2004	NON-COMPETING CONTINUATION	$183,167
														Subtotal = $183,167

Issue Date FY: 2003 ( Subtotal = $183,167 )
2003	2003	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Alcohol Research Programs	000	2	6/27/2003	NON-COMPETING CONTINUATION	$183,167
														Subtotal = $183,167

Issue Date FY: 2002 ( Subtotal = $211,017 )
2002	2002	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Alcohol Research Programs	000	1	7/1/2002	NEW	$211,017
														Subtotal = $211,017

Grand Total All Awards = $2,259,531

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Effects of Ethanol TNF Induced Cytotoxicity

Award Number: R01AA012897

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: 12/01/2000

PERIOD OF PERFORMANCE END DATE: 02/29/2016

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