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Redox regulation in myocardial disease

Award Number: R01AG023039
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2004
PERIOD OF PERFORMANCE END DATE: 01/31/2019

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Redox regulation in myocardial disease - DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) play both physiological and pathological roles in the heart and critically regulate survival and death of cardiomyocytes (CMs). NADPH oxidases purposefully produce ROS, including superoxide and hydrogen peroxide, by transferring electrons from NADPH or NADH to molecular oxygen. We have been focusing on NADPH oxidase 4 (Nox4), one of the major NADPH oxidase isoforms expressed in intracellular membranes in the heart, and we have discovered its key features. Excessive activation of Nox4 in response to hypertrophic stimuli, aging, and ischemia/reperfusion (I/R) leads to increases in oxidative stress, mitochondrial dysfunction, CM cell death, and cardiac dysfunction. On the other hand, basal production of ROS by either Nox2 or Nox4 during ischemia and reperfusion acts as a physiological second messenger to induce hypoxic adaptation. These studies suggest that the activity of Nox4 is supposed to be kept at appropriate levels in order to avoid accumulation of ROS either above or below physiological levels. How the activity of Nox4 is controlled in CMs under various pathophysiological conditions is poorly understood. Nox4 is believed to be regulated primarily at the level of transcription/translation. However, using yeast two-hybrid screening, we have identified that Nox4 physically associates with Fyn, a non-receptor type tyrosine kinase and that Fyn- mediated phosphorylation of Nox4 negatively regulates Nox4 and serves as an important negative feedback mechanism to limit excessive oxidative stress in the heart. We here test our hypotheses 1) that Fyn-mediated phosphorylation of Nox4 at Y566 inhibits interaction between Nox4 and p22phox and negatively regulates ROS production by Nox4, and 2) that activation of endogenous Fyn in response to PO and ischemic preconditioning (IPC) induces phosphorylation/suppression of Nox4 at Y566, thereby attenuating the NADPH oxidase activity of Nox4 and protecting the heart from PO and I/R injury. Using both molecular signaling and in vivo physiology approaches, we will show the molecular mechanism of the Fyn-mediated suppression of Nox4 and the functional significance of Fyn-mediated regulation of Nox4 during PO and IPC in vivo. Our study will elucidate a novel and direct PTM mechanism by which Nox4, the major ROS-producing enzyme in the heart, is regulated by stress and its functional significance during cardiac conditions frequently associated with aging. Our study will provide an important clue to better control the activity of Nox4 in the heart during cardiac stress in cardiovascular patients.


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: 2018 ( Subtotal = $389,599 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	16	1/11/2018	NON-COMPETING CONTINUATION	$350,639
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	001	16	4/11/2018	NON-COMPETING CONTINUATION	$38,960
														Subtotal = $389,599

Issue Date FY: 2017 ( Subtotal = $389,599 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	001	15	6/13/2017	NON-COMPETING CONTINUATION	$38,960
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	15	1/3/2017	NON-COMPETING CONTINUATION	$350,639
														Subtotal = $389,599

Issue Date FY: 2016 ( Subtotal = $389,599 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Aging Research	000	14	2/16/2016	NON-COMPETING CONTINUATION	$389,599
														Subtotal = $389,599

Issue Date FY: 2015 ( Subtotal = $377,910 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Aging Research	000	13	2/18/2015	NON-COMPETING CONTINUATION	$377,910
														Subtotal = $377,910

Issue Date FY: 2014 ( Subtotal = $389,599 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Aging Research	002	12	4/30/2014	COMPETING CONTINUATION	$389,599
2014	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	001	10	1/24/2014	NON-COMPETING CONTINUATION	$27,527
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Aging Research	000	11	1/23/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$27,527
														Subtotal = $389,599

Issue Date FY: 2013 ( Subtotal = $325,904 )
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	000	10	1/17/2013	NON-COMPETING CONTINUATION	$310,384
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	005	10	1/24/2014	NON-COMPETING CONTINUATION	$27,527
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	002	10	8/21/2013	NON-COMPETING CONTINUATION	-$269,732
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Aging Research	004	11	1/23/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$27,527
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Aging Research	003	11	8/22/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$269,732
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	001	10	5/28/2013	NON-COMPETING CONTINUATION	$15,520
														Subtotal = $325,904

Issue Date FY: 2012 ( Subtotal = $350,832 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	000	9	2/9/2012	NON-COMPETING CONTINUATION	$350,832
														Subtotal = $350,832

Issue Date FY: 2011 ( Subtotal = $374,323 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	001	8	6/17/2011	NON-COMPETING CONTINUATION	$23,833
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	000	8	2/1/2011	NON-COMPETING CONTINUATION	$350,490
														Subtotal = $374,323

Issue Date FY: 2010 ( Subtotal = $377,284 )
2010	2010	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	000	7	3/4/2010	NON-COMPETING CONTINUATION	$377,284
														Subtotal = $377,284

Issue Date FY: 2009 ( Subtotal = $538,265 )
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	001	6	9/16/2009	SUPPLEMENT FOR EXPANSION	$155,276
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Aging Research	000	6	2/4/2009	COMPETING CONTINUATION	$382,989
														Subtotal = $538,265

Issue Date FY: 2008 ( Subtotal = $361,233 )
2008	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Aging Research	000	5	2/20/2008	NON-COMPETING CONTINUATION	$361,233
														Subtotal = $361,233

Issue Date FY: 2007 ( Subtotal = $368,605 )
2007	2007	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Aging Research	000	4	2/26/2007	NON-COMPETING CONTINUATION	$368,605
														Subtotal = $368,605

Issue Date FY: 2006 ( Subtotal = $379,614 )
2006	2006	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Aging Research	000	3	1/25/2006	NON-COMPETING CONTINUATION	$379,614
														Subtotal = $379,614

Issue Date FY: 2005 ( Subtotal = $388,750 )
2005	2005	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Aging Research	000	2	1/21/2005	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2004 ( Subtotal = $388,750 )
2004	2004	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Aging Research	000	1	2/11/2004	NEW	$388,750
														Subtotal = $388,750

Grand Total All Awards = $5,789,866

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Redox regulation in myocardial disease

Award Number: R01AG023039

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2004

PERIOD OF PERFORMANCE END DATE: 01/31/2019

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