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The molecular determinants of atrial fibrillation

Award Number: K99HL173573
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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The molecular determinants of atrial fibrillation - PROJECT SUMMARY/ ABSTRACT Atrial Fibrillation (AF) is an arrhythmia characterized by the aberrant, unorganized initiation and propagation of electrical impulses across the atria. The most common serious arrhythmia, AF affected an estimated 33.5 million globally in 2010, with a lifetime risk of 1 in 3 individuals older than 55 years old. A greater understanding of the mechanisms of AF is required to design more effective treatment strategies. Genome-wide association studies have linked AF with over 143 genomic loci, including the transcription factor (TF) TBX5. In our previous study, we integrated single-nucleus RNA- and ATAC- sequencing (multiomics) of control and Tbx5 KO aCMs with TBX5 chromatin occupancy in aCMs to identify direct TBX5 targets that might contribute to AF. In the process, we uncovered a novel function for TBX5 in maintaining genomic accessibility at enhancer elements, likely by recruiting chromatin modifying proteins. TBX5 interacts with chromodomain helicase DNA binding protein 4 (CHD4), a component of the nucleosome remodeling and histone deacetylase (NuRD) complex. Although conventionally viewed as a transcriptional repressor, our Preliminary Data reveal an exciting, alternative role for CHD4 as a transcriptional activator. To better understand gene expression changes central to AF, we performed multiomics on a second AF mouse model caused by Liver Kinase B1 (LKB1) inactivation in aCMs, a gene decreased in human AF patient aCMs, revealing 632 core atrial rhythm (AR) genes that are commonly downregulated in aCMs from both models. 61% of AR genes were adjacent to regions co-occupied by CHD4-TBX5, and include the Na+ channel SCN5A, regulators FGF12/13 and the gap junction channels Connexin 43 (GJA1) and Connexin 45 (GJA5). These data lead to our central hypothesis that CHD4 maintains rhythm homeostasis in healthy atria by complexing with TBX5 to maintain the accessibility of TBX5-dependent enhancers, promoting the expression of genes that are critical for normal aCM electrical function. To determine the mechanisms by which the CHD4-TBX5 complex regulates the atrial enhancer network, we will characterize the phenotypic and genomic consequences of Chd4 inactivation in aCMs, identify CHD4- interacting proteins required for aCM gene activation, and uncover other cis-activating factors that function cooperatively with CHD4-TBX5 to regulate aCM gene expression. To identify core atrial genes required for atrial rhythm, we will test the requirement of select AR genes to maintain atrial rhythm by inactivation. Genes identified as critical regulators of rhythm will then be evaluated for therapeutic efficacy in AF prevention and reversal in our established AF mouse models. This proposal is significant because it will mechanistically characterize genes required for atrial function, determine how they are regulated, and test their potential as therapies in multiple models, laying the groundwork for the development of more effective treatment strategies.


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 = $0 )
2026	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	1/18/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $122,839 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	4/8/2025	NON-COMPETING CONTINUATION	$122,839
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	2	8/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $122,839

Issue Date FY: 2024 ( Subtotal = $122,839 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	3/28/2024	NEW	$122,839
														Subtotal = $122,839

Grand Total All Awards = $245,678

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The molecular determinants of atrial fibrillation

Award Number: K99HL173573

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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