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Regulation of myocardial growth and death by autophagy

Award Number: R01HL102738
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2010
PERIOD OF PERFORMANCE END DATE: 03/31/2015

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Regulation of myocardial growth and death by autophagy - DESCRIPTION (provided by applicant): Autophagy is a major mechanism of degradation for long-lived proteins and intracellular organelles. Autophagy plays an adaptive role under energy starvation, such as myocardial ischemia, thereby mediating cell survival, whereas autophagy associates with programmed cell death under some pathological conditions, such as reperfusion injury. Thus, it is essential to elucidate the function of autophagy in various pathophysiological conditions and to determine how autophagy is regulated in the heart. In a mouse model of myocardial infarction (MI), induced by permanent coronary ligation (PCL), although excessive activation of autophagy increases the mortality at an acute phase, downregulation of autophagy leads to cardiac dysfunction at a chronic phase. Mammalian sterile 20 like kinase 1 (Mst1), a potent stimulator of apoptosis and heart failure, strongly inhibits autophagy whereas FoxO1, which is activated by nutrient starvation and cardiac unloading, stimulates autophagy. The overall goal of this project is to elucidate both physiological and pathological functions of autophagy in the heart under stress and how autophagy is regulated by stress responsive signaling mechanisms in the heart. We hypothesize that: A) Strong induction of autophagy by Beclin 1 at an acute phase of MI is detrimental, whereas autophagy induced by FoxO1 at a chronic phase of MI is adaptive. B) Mst1 acts as an endogenous inhibitor of autophagy through direct protein-protein interaction with Beclin1, thereby causing an accumulation of protein aggregates through p62, an ubiquitin interacting protein. C) FoxOs are either deacetylated or upregulated by starvation and cardiac unloading and plays an essential role in mediating adaptive autophagy. These hypotheses will be tested, using (1) established experimental methods to evaluate autophagosome formation and autophagic flux in vitro and in vivo, (2) unique genetically altered mouse models, including cardiac specific and inducible Beclin1 knock down, atg7 KO, and FoxO1 KO mice and systemic p62 KO mice, (3) the mouse models of PCL and aortic debanding, (4) shRNA-mediated knock- down and proteomics. Our study will elucidate the role of autophagy in mediating both physiological and pathological functions under stresses and underlying signaling mechanisms regulating autophagy in the heart.


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: 2014 ( Subtotal = $497,680 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	000	6	3/4/2014	NON-COMPETING CONTINUATION	$497,680
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cardiovascular Diseases Research	002	5	4/21/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$8,878
2014	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	4	4/21/2014	NON-COMPETING CONTINUATION	$8,878
														Subtotal = $497,680

Issue Date FY: 2013 ( Subtotal = $474,338 )
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cardiovascular Diseases Research	005	5	4/21/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$8,878
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	004	4	4/21/2014	NON-COMPETING CONTINUATION	$8,878
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	002	4	8/22/2013	NON-COMPETING CONTINUATION	-$467,938
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	4	4/6/2013	NON-COMPETING CONTINUATION	$448,430
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	4	7/9/2013	NON-COMPETING CONTINUATION	$25,908
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cardiovascular Diseases Research	003	5	8/22/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$467,938
														Subtotal = $474,338

Issue Date FY: 2012 ( Subtotal = $498,255 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	3	3/23/2012	NON-COMPETING CONTINUATION	$498,255
														Subtotal = $498,255

Issue Date FY: 2011 ( Subtotal = $498,255 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	2	3/15/2011	NON-COMPETING CONTINUATION	$467,523
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	001	2	6/21/2011	NON-COMPETING CONTINUATION	$30,732
														Subtotal = $498,255

Issue Date FY: 2010 ( Subtotal = $503,286 )
2010	2010	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cardiovascular Diseases Research	000	1	4/12/2010	NEW	$503,286
														Subtotal = $503,286

Grand Total All Awards = $2,471,814

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Regulation of myocardial growth and death by autophagy

Award Number: R01HL102738

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2010

PERIOD OF PERFORMANCE END DATE: 03/31/2015

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