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Viral subversion of intercellular coupling during myocarditis

Award Number: R01HL159512
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Viral subversion of intercellular coupling during myocarditis - SUMMARY Cardiovascular disease remains the principal cause of death in the United States, with myocarditis contributing to 42% of all sudden deaths in young adults. Human adenovirus type 5 is a leading etiological agent of viral myocarditis, yet research is lacking due to host species specificity limiting the development of model systems for cardiac infection. The effect of active adenoviral infection on cardiomyocyte function and arrhythmogenesis that precedes immune responses and progression to heart failure is unknown. Gap junctions, predominantly comprising the protein connexin43 (Cx43) in the ventricular intercalated disc, facilitate action potential propagation during each heartbeat. An intimate association and interplay between gap junctions, other ID resident ion channels, and components of mechanical junctions is now well accepted. Alterations in ID mechanical and electrical coupling cause arrhythmias, and while it has been demonstrated that adenovirus directly targets adhesion late in infection, the relationship between adenoviral myocarditis and Cx43 gap junction, or other ion channel, function and regulation remains unexplored. Indeed, treatment for viral myocarditis is largely supportive, with no therapeutic interventions or antivirals demonstrating significant clinical efficacy to date. Through study of adenoviral infection of cardiac muscle at the molecular level, we will address significant gaps in the knowledge regarding mechanisms underlying the impact of infection on cardiomyocyte intercellular coupling and electrophysiology while identifying therapeutic targets to limit viral spread and/or rescue electrical coupling in diseased hearts. Our long term goal is to elucidate the pathological mechanisms of viral myocarditis and resulting arrhythmogenic subversion of cardiac ion channels and junctional structures. The objective of this R01 proposal is to determine how electrical and mechanical intercellular coupling is affected during acute adenoviral cardiac infection to precipitate an arrhythmogenic substrate. Our central hypothesis is that adenovirus hijacks junction protein expression and function leading to an arrhythmogenic substrate prior to gross pathological remodeling and the appreciable host immune responses. We will test this hypothesis with the following two Specific Aims: Aim 1: Determine the role of early adenoviral proteins in generation of an arrhythmogenic cellular landscape. The working hypothesis for this aim is that early adenoviral proteins activate a PI3K/β-catenin signaling axis targeting Cx43 and cardiac ion channel function, contributing to arrhythmogenesis. Aim 2: Determine the role of connexins and gap junction intercellular communication in adenoviral pathogenesis. The working hypothesis for this aim is that adenovirus stabilizes cellular junctions to facilitate viral spread while limiting intercellular communication to enhance viral replication.


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 = $538,404 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cardiovascular Diseases Research	000	4	9/4/2025	NON-COMPETING CONTINUATION	$538,404
														Subtotal = $538,404

Issue Date FY: 2024 ( Subtotal = $527,635 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cardiovascular Diseases Research	000	3	6/18/2024	NON-COMPETING CONTINUATION	$527,635
														Subtotal = $527,635

Issue Date FY: 2023 ( Subtotal = $538,404 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cardiovascular Diseases Research	000	2	7/22/2023	NON-COMPETING CONTINUATION	$538,404
														Subtotal = $538,404

Issue Date FY: 2022 ( Subtotal = $546,830 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cardiovascular Diseases Research	000	1	6/30/2022	NEW	$546,830
														Subtotal = $546,830

Grand Total All Awards = $2,151,273

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Viral subversion of intercellular coupling during myocarditis

Award Number: R01HL159512

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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