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Acid, Succinate and Glyoxal Metabolism in Ischemia

Award Number: R01HL071158
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2003
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Acid, Succinate and Glyoxal Metabolism in Ischemia - ABSTRACT In the US there are >700,000 new heart attacks (acute myocardial infarctions) a year, and >300,000 patients undergo scheduled ischemia during cardiac surgery. Beyond tissue reperfusion (angioplasty, thrombolysis) there are no FDA-approved interventions to limit acute cardiac injury due to ischemia and reperfusion (IR). This renewal proposal supports our ongoing research program in cardiac metabolism, and is focused on novel cardioprotective metabolic signaling events downstream of glycolysis. It is built on the following premise: (i) Acidic pH during IR is cardioprotective, and many therapies that boost glycolysis work in-part by enhancing metabolic acidosis. (ii) Succinate accumulation is a key event in ischemia, and its oxidation at reperfusion drives reactive oxygen species generation. We propose acid can regulate succinate dynamics (accumulation, oxidation, transport). (iii) The glycolytic byproduct methylglyoxal (MGO) causes glycative stress in diabetes, but type-I diabetic hearts are acutely protected against IR injury, and MGO inhibits the mitochondrial permeability transition (PT) pore, a key event in IR injury. Some cardioprotective interventions also elevate MGO. (iv) The mitochondrial enzyme ALKBH7 is necessary for necrosis. Inhibition or ablation of ALKBH7 is cardioprotective, and this protection requires the MGO metabolizing enzyme GLO-1. Based on these published and preliminary findings, our central hypothesis is that the cardioprotective effects of elevated glycolysis are mediated by pH, succinate, and MGO. This hypothesis will be tested by addressing 3 related aims… Aim 1 will investigate succinate dynamics in IR injury and the impact of pH. Aim 2 will investigate the role of MGO as an acute cardioprotective signal, including identifying its targets in mitochondria. Aim 3 will study ALKBH7, identify its substrates, and develop ALKBH7 inhibitors as cardioprotective drugs. The aims will use established experimental systems (adult cardiomyocytes, perfused hearts, LC-MS based metabolomics, in-vivo IR injury, and a high-fat diet model of diabetes) and engineered mice including Alkbh7-/-, Glo1-/- and hGlo1TG. Innovation is embedded in the idea that MGO can serve an acute protective signaling role separate from its well-known chronic pathologic effects (i.e. hormesis). This work will advance basic knowledge on ischemic cardiac metabolism, will develop small molecule therapeutics, and will offer mechanistic insights to other pathologies beyond IR.


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 = $383,210 )
2025	2025	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Cardiovascular Diseases Research	000	22	4/15/2025	NON-COMPETING CONTINUATION	$383,210
														Subtotal = $383,210

Issue Date FY: 2024 ( Subtotal = $414,128 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Cardiovascular Diseases Research	000	21	3/4/2024	NON-COMPETING CONTINUATION	$380,322
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Cardiovascular Diseases Research	001	21	6/22/2024	NON-COMPETING CONTINUATION	$33,806
														Subtotal = $414,128

Issue Date FY: 2023 ( Subtotal = $419,461 )
2023	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Cardiovascular Diseases Research	000	20	3/22/2023	NON-COMPETING CONTINUATION	$419,461
														Subtotal = $419,461

Issue Date FY: 2022 ( Subtotal = $416,434 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	001	19	3/6/2022	COMPETING CONTINUATION	$416,434
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	003	19	7/12/2022	COMPETING CONTINUATION	$8,116
2022	2020	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	000	18	2/28/2022	NON-COMPETING CONTINUATION	$0
2022	2020	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	002	18	7/12/2022	NON-COMPETING CONTINUATION	-$8,116
														Subtotal = $416,434

Issue Date FY: 2020 ( Subtotal = $385,000 )
2020	2020	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	000	18	5/18/2020	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2019 ( Subtotal = $385,000 )
2019	2019	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	000	17	5/22/2019	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2018 ( Subtotal = $385,000 )
2018	2018	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	002	16	6/13/2018	NON-COMPETING CONTINUATION	$385,000
2018	2017	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	001	15	12/9/2017	COMPETING CONTINUATION	$7,706
2018	2016	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	000	14	12/9/2017	EXTENSION WITH OR WITHOUT FUNDS	-$7,706
														Subtotal = $385,000

Issue Date FY: 2017 ( Subtotal = $385,000 )
2017	2017	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	001	15	7/21/2017	COMPETING CONTINUATION	$385,000
2017	2016	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cardiovascular Diseases Research	000	14	7/19/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $385,000

Issue Date FY: 2016 ( Subtotal = $383,750 )
2016	2016	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	000	14	5/20/2016	EXTENSION WITH OR WITHOUT FUNDS	$383,750
														Subtotal = $383,750

Issue Date FY: 2015 ( Subtotal = $377,993 )
2015	2015	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	000	13	4/23/2015	NON-COMPETING CONTINUATION	$377,993
														Subtotal = $377,993

Issue Date FY: 2014 ( Subtotal = $376,075 )
2014	2014	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	000	12	5/28/2014	NON-COMPETING CONTINUATION	$376,075
														Subtotal = $376,075

Issue Date FY: 2013 ( Subtotal = $365,330 )
2013	2013	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	000	11	8/8/2013	COMPETING CONTINUATION	$365,330
														Subtotal = $365,330

Issue Date FY: 2012 ( Subtotal = $343,035 )
2012	2012	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	000	10	12/9/2011	NON-COMPETING CONTINUATION	$308,732
2012	2012	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	001	10	3/27/2012	NON-COMPETING CONTINUATION	$34,303
														Subtotal = $343,035

Issue Date FY: 2011 ( Subtotal = $346,500 )
2011	2011	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	000	9	12/17/2010	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $346,500

Issue Date FY: 2010 ( Subtotal = $346,500 )
2010	2010	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	000	8	12/29/2009	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $346,500

Issue Date FY: 2009 ( Subtotal = $346,500 )
2009	2009	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14642	MONROE	USA	Cardiovascular Diseases Research	000	7	12/23/2008	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $346,500

Issue Date FY: 2008 ( Subtotal = $346,500 )
2008	2008	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Cardiovascular Diseases Research	000	6	1/10/2008	COMPETING CONTINUATION	$346,500
														Subtotal = $346,500

Issue Date FY: 2006 ( Subtotal = $307,598 )
2006	2006	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Cardiovascular Diseases Research	000	5	7/14/2006	NON-COMPETING CONTINUATION	$307,598
														Subtotal = $307,598

Issue Date FY: 2005 ( Subtotal = $315,000 )
2005	2005	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Cardiovascular Diseases Research	000	4	7/15/2005	NON-COMPETING CONTINUATION	$315,000
														Subtotal = $315,000

Issue Date FY: 2004 ( Subtotal = $315,000 )
2004	2004	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Cardiovascular Diseases Research	000	3	7/29/2004	NON-COMPETING CONTINUATION	$315,000
														Subtotal = $315,000

Issue Date FY: 2003 ( Subtotal = $315,000 ) (Continued on the next page)
2003	2003	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Cardiovascular Diseases Research	000	2	7/31/2003	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$315,000
Grand Total All Awards = $7,658,014

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Acid, Succinate and Glyoxal Metabolism in Ischemia

Award Number: R01HL071158

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2003

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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