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The Molecular Basis for Impaired Intercellular Electrical Signaling in Atrial Fibrillation

Award Number: F30HL184855
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/15/2027
PERIOD OF PERFORMANCE END DATE: 03/14/2028

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The Molecular Basis for Impaired Intercellular Electrical Signaling in Atrial Fibrillation - THE MOLECULAR BASIS FOR IMPAIRED INTERCELLULAR ELECTRICAL SIGNALING IN ATRIAL FIBRILLATION PROJECT SUMMARY Atrial fibrillation (AF) is the most common cardiac arrhythmia with a prevalence of 10 million cases in the US, corresponding to over 4% of the adult population. Atrial fibrillation is one of the most common causes of stroke and increases the risks associated with heart failure, myocardial infarction, chronic kidney disease and dementia. Current therapeutic and surgical approaches are lacking. Despite this, no new antiarrhythmic therapies have been introduced in over a decade. Risk of introducing fatal ventricular arrhythmias remains a pressing concern. In order to target AF, it is vital to identify tissue-specific targets unique to atrial tissue. Connexins, which mediate electrical communication in the heart, offer a promising avenue for selective targeting. Connexin proteins assemble as intercellular gap junction channels (GJCs). The central large pore mediates communication between cells of a tissue with a molecular size limit of ~1,000 Daltons. In the heart, gap junction channels are essential for action potential propagation and coordinated contraction. Their role in the pathogenesis of AF is thought to occur by slowing conduction velocity so as to promote re-entry circuits. Three connexin (Cx) isoforms are present in the heart: Cx45 in pacemaker cells, Cx40 in atrial myocardium and the conduction system, and Cx43 in ventricular myocardium. The tissue-specific distribution of connexins and their respective conductances are likely important for coordinating current flow in the heart. How connexin channel structure confers these effects remains unclear. Comparative high-resolution structures of Cx40 and Cx45 versus Cx43 may elucidate these electrophysiological observations. Moreover, resolved structures of all three cardiac isoforms would aid in the development of targeted therapeutics. The goal of this fellowship is to solve the structures of Cx40 and Cx45, and to use these structural observations to understand differences in conductance, ion selectivity, and voltage- sensitivity that drive cardiac conduction. An additional goal will focus on Cx40, for which 15 mutations have been identified that increase the risk for atrial fibrillation. This proposal aims to use an integrated approach combining structure and computational analysis to explore the molecular basis for the role that Cx40 mutations play in atrial fibrillation. Mass spectrometry will be used to examine the conformational dynamics of the mutant versus wild type channels. Lastly, molecular dynamics simulation will integrate the data and explore possible conformations that may affect conductance. The hypothesis is that pore-lining amino-acid residues are crucial for mediating conductance and that pathogenic AF mutations lining the pore of Cx40 GJCs will have the greatest impact on conductance. We expect that our results will yield insight for designing novel antiarrhythmics for atrial fibrillation.


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: 2026 ( Subtotal = $55,114 )
2026	2026	UNIVERSITY OF MIAMI	6200 SAN AMARO DR STE 430	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cardiovascular Diseases Research	000	1	9/17/2026	NEW	$55,114
														Subtotal = $55,114

Grand Total All Awards = $55,114

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The Molecular Basis for Impaired Intercellular Electrical Signaling in Atrial Fibrillation

Award Number: F30HL184855

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/15/2027

PERIOD OF PERFORMANCE END DATE: 03/14/2028

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