Sunday, November 24, 2024 11/24/2024

Sex/estrogen-dependent vulnerability to alcohol-evoked cardiotoxicity: Role of circadian rhythm regulated enzymes

Award Number: R01AA014441
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

Here, we seek to understand the role of central and cardiac circadian rhythm in the sex/estrogen (E2)-dependent vulnerability to alcohol-evoked cardiotoxicity. This overlooked translational research is timely because young women's alcohol consumption is rapidly increasing despite their higher sensitivity to the cardiotoxic effect of alcohol, compared to men. While limited (mostly generated in non-cardiovascular tissues) data support our scientific premise, there are no studies on whether E2-circardian rhythm interaction in the heart or autonomic nuclei regulates cardiac redox enzyme and function via heart specific miRNAs, particularly in the presence of alcohol. We hypothesize that ethanol disruption of the E2/estrogen receptor (ER) modulation of the circadian rhythm (PERIOD genes; Per1/Per2)-regulated redox enzymes paradoxically transforms E2 into a pro-inflammatory hormone. Specifically, we will elucidate the unresolved role of the ERα-Per2 dependent divergent upregulation of cardiac catalase and aldehyde dehydrogenase (ALDH2), and downregulation of hemeoxygenase (HO-1), in this female health related problem. We will focus on these cardiac enzymes, and heart-specific miRNAs that mediate protection or injury. Notably, catalase and ALDH2 regulate the cellular redox status and cell survival as well as oxidative metabolism of ethanol. To test our novel hypotheses, we assembled a capable research team to execute a multidimensional approach encompassing integrative cardiovascular, genetic, cellular and pharmacological studies. These studies will yield new insights into the role of the circadian rhythm in E2-dependent cardioprotection and ethanol-induced cardiotoxicity as well as identifying novel therapeutics for mitigating the chronic cardiovascular anomalies caused by alcohol in females. The two logically overlapping areas to be investigated in this project are: Aim 1 studies will test the hypothesis that disruption of the E2/ERα-Per2 loop regulation of redox enzymes and heart specific miRNAs mediate ethanol-evoked myocardial oxidative stress/dysfunction in females. Multilevel studies in rat models sensitive, or resistant, to ethanol-evoked myocardial dysfunction, and in genetic models (ERα/ ERβ/GPER KO and Per2 loss of function, mPer2, mice) will generate robust data to test our hypothesis. Aim 2 studies will test the hypothesis that concomitant ethanol-evoked cardiac BH4 depletion/eNOS uncoupling and E2/Per2 divergent regulation of HO-1 and catalase trigger the death associated protein kinase-3 (DAPK-3) signaling cascade to cause myocardial oxidative stress/dysfunction. We will also identify cell signaling cascades as novel therapeutic targets for alleviating the E2/circadian rhythm-dependent cardiovascular derangements caused by chronic ethanol in females.


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 = -$1,852 )
2025	2022	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	15	10/24/2024	NON-COMPETING CONTINUATION	-$1,852
														Subtotal = -$1,852

Issue Date FY: 2022 ( Subtotal = $385,314 )
2022	2022	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	15	7/26/2022	NON-COMPETING CONTINUATION	$385,314
														Subtotal = $385,314

Issue Date FY: 2021 ( Subtotal = $385,314 )
2021	2021	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	14	7/22/2021	NON-COMPETING CONTINUATION	$385,314
														Subtotal = $385,314

Issue Date FY: 2020 ( Subtotal = $385,314 )
2020	2020	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	13	7/24/2020	NON-COMPETING CONTINUATION	$385,314
														Subtotal = $385,314

Issue Date FY: 2019 ( Subtotal = $385,314 )
2019	2019	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	12	7/31/2019	NON-COMPETING CONTINUATION	$385,314
														Subtotal = $385,314

Issue Date FY: 2018 ( Subtotal = $385,314 )
2018	2018	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	001	11	8/24/2018	COMPETING CONTINUATION	$385,314
2018	2015	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	10	6/25/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $385,314

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	10	6/2/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $327,362 )
2015	2015	EAST CAROLINA UNIVERSITY	2200 S Charles Boulevard	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	10	6/11/2015	NON-COMPETING CONTINUATION	$327,362
														Subtotal = $327,362

Issue Date FY: 2014 ( Subtotal = $327,677 )
2014	2014	EAST CAROLINA UNIVERSITY	2200 S Charles Boulevard	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	9	6/11/2014	NON-COMPETING CONTINUATION	$327,677
														Subtotal = $327,677

Issue Date FY: 2013 ( Subtotal = $314,450 )
2013	2013	EAST CAROLINA UNIVERSITY	RAGSDALE BUILDING	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	8	7/2/2013	NON-COMPETING CONTINUATION	$314,450
														Subtotal = $314,450

Issue Date FY: 2012 ( Subtotal = $338,120 )
2012	2012	EAST CAROLINA UNIVERSITY	RAGSDALE BUILDING	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	7	6/20/2012	NON-COMPETING CONTINUATION	$338,120
														Subtotal = $338,120

Issue Date FY: 2011 ( Subtotal = $353,479 )
2011	2011	EAST CAROLINA UNIVERSITY	RAGSDALE BUILDING	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	6	9/5/2011	COMPETING CONTINUATION	$353,479
														Subtotal = $353,479

Issue Date FY: 2010 ( Subtotal = $0 )
2010	2008	EAST CAROLINA UNIVERSITY	RAGSDALE BUILDING	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	5	6/30/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $320,900 )
2008	2008	EAST CAROLINA UNIVERSITY	RAGSDALE BUILDING	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	5	3/28/2008	NON-COMPETING CONTINUATION	$320,900
														Subtotal = $320,900

Issue Date FY: 2007 ( Subtotal = $320,900 )
2007	2007	EAST CAROLINA UNIVERSITY	RAGSDALE BUILDING	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	4	3/19/2007	NON-COMPETING CONTINUATION	$320,900
														Subtotal = $320,900

Issue Date FY: 2006 ( Subtotal = $330,485 )
2006	2006	EAST CAROLINA UNIVERSITY	RAGSDALE BUILDING	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	3	1/30/2006	NON-COMPETING CONTINUATION	$330,485
														Subtotal = $330,485

Issue Date FY: 2005 ( Subtotal = $338,438 )
2005	2005	EAST CAROLINA UNIVERSITY	RAGSDALE BUILDING	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	2	3/28/2005	NON-COMPETING CONTINUATION	$338,438
														Subtotal = $338,438

Issue Date FY: 2004 ( Subtotal = $338,438 )
2004	2004	EAST CAROLINA UNIVERSITY	RAGSDALE BUILDING	GREENVILLE	NC	27858	PITT	USA	Alcohol Research Programs	000	1	4/29/2004	NEW	$338,438
														Subtotal = $338,438

Grand Total All Awards = $5,234,967

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Sex/estrogen-dependent vulnerability to alcohol-evoked cardiotoxicity: Role of circadian rhythm regulated enzymes

Award Number: R01AA014441

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer