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Regulation of the Cardiac Sodium Channel by Sumoylation

Award Number: R01HL115955
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2013
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Regulation of the Cardiac Sodium Channel by Sumoylation - The cardiac Na+ channel SCN5A (Nav1.5) and the inward depolarizing Na+ current (INa) play a critical role in regulating the action potential of myocytes in the atrium, ventricle, and specialized conduction system. Mutations in SCN5A are associated with several arrhythmia phenotypes including long QT syndrome, Brugada syndrome, and dilated cardiomyopathy. In addition, loss of Na+ channel function is observed during heart failure, leading to conduction slowing and ventricular arrhythmias based on re-entrant mechanisms. Small Ubiquitin-like Modifiers (SUMOs), post-translationally modify lysine residues on proteins. Decrease in SUMOylation of cardiac calcium-handling proteins is associated with human heart failure. The significance of SUMOylation in regulating cardiac electrical activity is not known. Our preliminary data identifies a polymorphism in the SUMO1 gene that associates with appropriate defibrillator shocks in patients with heart failure, suggesting that SUMO1 modifies arrhythmia risk. Given our prior work demonstrating that acetylation of SCN5A on a lysine residue decreases cardiac sodium current, we now hypothesize that in addition to acetylation, SCN5A is post-translationally modified by SUMOylation, and SUMO-SCN5A is vital for the cardiac Na+ current and for normal electrical activity in the heart. This hypothesis is based on very novel preliminary data that SUMO1 modifies SCN5A and stimulates the Na+ current, whereas de-SUMOylation inhibits INa and precipitates cardiac arrhythmias in vivo. This application will explore in-depth the role of SUMOylation and de-SUMOylation on the cardiac Na+ current , characterizing their effect on channels properties, expression, ubiquitination, acetylation, trafficking, and interaction with its known partner Sirtuin1. The proposal will identify the lysine residues in SCN5A that are SUMOylated, and explore the importance of SUMOylation of these lysines on the cardiac Na+ current. It will develop and use state-of-the-art biological reagents, including a novel non-SUMOylatable Nav1.5 knockin mouse, cardiotropic viral vectors to SUMOylate and de-SUMOylate Nav1.5 in vivo, and transgenic mice overexpressing SUMO proteins. It will leverage the expertise of basic and mouse electrophysiologists, molecular biologists, and experts in cardiac SUMOylation. Using these reagents, and with the collective expertise of the investigative team, it will determine if SCN5A SUMOylation is altered in heart failure, and if cardiac SUMOylation modifies arrhythmic risk in failing and non-failing hearts. SUMO modification of SCN5A will identify a new mechanism for regulation of cardiac INa, and one that has potential clinical relevance in patients with heart failure. In doing so, it will open the door for using SUMO proteins as therapeutic agents in patients at risk for cardiac arrhythmias.


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: 2023 ( Subtotal = $636,662 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	8	7/13/2023	NON-COMPETING CONTINUATION	$636,662
														Subtotal = $636,662

Issue Date FY: 2022 ( Subtotal = $1,022,912 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	002	7	9/21/2022	NON-COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	001	7	8/12/2022	SUPPLEMENT FOR EXPANSION	$386,250
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	003	7	9/22/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	7	8/9/2022	NON-COMPETING CONTINUATION	$636,662
														Subtotal = $1,022,912

Issue Date FY: 2021 ( Subtotal = $644,387 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	6	7/11/2021	NON-COMPETING CONTINUATION	$644,387
														Subtotal = $644,387

Issue Date FY: 2020 ( Subtotal = $682,547 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	5	5/28/2020	COMPETING CONTINUATION	$682,547
														Subtotal = $682,547

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	4	8/9/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $619,966 )
2016	2016	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	4	5/26/2016	EXTENSION WITH OR WITHOUT FUNDS	$619,966
														Subtotal = $619,966

Issue Date FY: 2015 ( Subtotal = $610,665 )
2015	2015	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	3	5/15/2015	NON-COMPETING CONTINUATION	$610,665
														Subtotal = $610,665

Issue Date FY: 2014 ( Subtotal = $611,469 )
2014	2014	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	2	5/22/2014	NON-COMPETING CONTINUATION	$611,469
														Subtotal = $611,469

Issue Date FY: 2013 ( Subtotal = $611,661 )
2013	2013	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	1	6/3/2013	NEW	$611,661
														Subtotal = $611,661

Grand Total All Awards = $5,440,269

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Regulation of the Cardiac Sodium Channel by Sumoylation

Award Number: R01HL115955

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2013

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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