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Targeting pathologic intracellular calcium release to prevent lethal arrhythmias

Award Number: F30HL168829
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Targeting pathologic intracellular calcium release to prevent lethal arrhythmias - PROJECT SUMMARY/ABSTRACT RyR2 is an intracellular calcium (Ca) release channel expressed in the sarcoplasmic reticulum (SR) of cardiomyocytes. In the normal heart, RyR2 Ca release from the SR is tightly regulated and only occurs during systole to facilitate heart contraction. In heart disease, RyR2 Ca release can occur during diastole and is considered pathologic. Pathologic Ca release can be caused by RyR2 mutations or RyR2 post-translational modifications. Pathologic Ca release during diastole reduces cardiac contractility due to depletion of SR Ca stores and is pro-arrhythmogenic due to delayed after-depolarizations resulting from sodium (Na) flux into the cell via the Na-Ca exchanger. RyR2 mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a genetic arrhythmia syndrome, while post-translational modifications have been widely documented in congestive heart failure (CHF) caused by myocardial infarction. Both conditions are associated with a high risk of sudden cardiac death (SCD). My mentor discovered that an old antiarrhythmic drug – flecainide – prevents pathologic rather than physiologic Ca release and is strikingly effective in preventing ventricular arrhythmias in CPVT patients. Importantly, he recently discovered that flecainide’s efficacy depends not on Na channel block but rather RyR2 block. Unfortunately, due to its Na channel blocking properties, flecainide increases mortality in patients with CHF and cannot be used in this patient population. To address these patients’ risk for SCD – currently unmitigated by available drugs – I aim to develop a flecainide analogue that maintains RyR2 block but not Na channel block. In doing so, I will investigate the mechanism of action of flecainide and test the hypothesis that its efficacy depends on a change in the membrane potential across the SR. My research background and the established use of patch clamp electrophysiology and calcium imaging in my mentor’s lab will enable me to test flecainide analogues generated by our collaborators in synthetic chemistry. To probe the mechanism of action underlying flecainide’s voltage-dependent RyR2 block, I will employ a variety of tools including genetically encoded voltage indicators and voltage-sensitive dyes to capture the theoretical membrane potential change that occurs at the SR. The results from this aim will not only clarify flecainide’s mechanism of action but also yield a novel therapeutic principle – that voltage-dependent block of RyR2 channels is a key feature for the development of future RyR2 inhibitors as antiarrhythmic drugs.


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 = $57,538 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	3	8/29/2025	NON-COMPETING CONTINUATION	$57,538
														Subtotal = $57,538

Issue Date FY: 2024 ( Subtotal = $56,351 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	6/7/2024	NON-COMPETING CONTINUATION	$56,351
														Subtotal = $56,351

Issue Date FY: 2023 ( Subtotal = $35,346 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	4/21/2023	NEW	$35,346
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	001	1	4/21/2023	NEW	$0
														Subtotal = $35,346

Grand Total All Awards = $149,235

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Targeting pathologic intracellular calcium release to prevent lethal arrhythmias

Award Number: F30HL168829

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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