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Investigating the role of SYNE1-Giant in Atrial Cardiomyopathy

Award Number: F31HL178278
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Investigating the role of SYNE1-Giant in Atrial Cardiomyopathy - PROJECT SUMMARY Atrial fibrillation (AF) and sinus node dysfunction (SND) are the most common heart rhythm disorders, affecting an estimated 6 million individuals in the US. Preventative and curative measures currently do not exist. The onset of AF and SND is preceded by the development of an arrythmia-associated pathogenic atrial substrate and understanding the mechanism governing the genesis of these disease-linked atrial substrates presents as a compelling therapeutic target prevailing hypothesis explaining the pathophysiology of diseased atrial substrates suggests that chronically elevated atrial stretch induces a maladaptive biomechanical stress response which results in both the dysregulation of gene expression pathways associated with the maintenance of atrial cardiomyocyte identity and a detrimental change in myocyte physiology and function. Within this context, the mechanosensitive molecules at the nuclear envelope, comprising the nuclear Lamins and the Linker of the Nucleoskeleton and Cytoskeleton (LINC-complex), emerge as novel potential targets. Numerous case reports of SYNE1, SYNE2, and Lamin mutations support this paradigm as reported mutations are strongly associated with cardiac myopathies where atrial fibrillation, conduction disease, and dilated cardiomyopathy are typically the earliest disease manifestations. Multiple GWAS studies have also identified common variants at the SYNE1, SYNE2, and Lamin A/C loci which are linked to atrial fibrillation. Integrated analysis of RNA-seq and Lamin A CHIP-seq data from monogenic Lamin A DCM patient-cardiomyocytes also demonstrated that heterochromatic Lamin-associated domains (LADs) are markedly reorganized in diseased human cardiomyocytes. Furthermore, we have identified a novel, de-novo mutation in the giant isoform of SYNE1 (R1812W) harbored by a patient with atrial standstill and ventricular dilation, and preliminary data suggests that the structure of the nuclear lamina is compromised in cardiomyocytes harboring this mutation. There is, therefore, strong evidence supporting a critical protective role for the LINC complex and force transmission across the nucleus in atrial cardiomyocytes, which when disrupted leads to heart rhythm disorders and cardiomyopathies. We hypothesize that SYNE1-Giant LINC-complexes buffer the nuclear lamina against mechanical load, and by this mechanism, disruption of SYNE1-Giant in the myocardium impairs nuclear structure and chromatin organization to drive pathological gene expression and cardiomyopathy. Accordingly, in the first aim of this proposal we will leverage SYNE1-Giant loss of function primary and iPSC-derived atrial cardiomyocytes (ACMs) to evaluate the consequence of SYNE1- Giant LINC-complex disruption on ACM nuclear morphology. In the second aim of this proposal, we will investigate whether SYNE1-Giant functions to maintain the structural, electrophysiological, and contractile properties of the atrial myocardium. To complete this aim, two we will utilize loss of function mouse models and generate atrial cardiac microtissues (CMTs) from SYNE1-Giant loss-of-function iPSC-ACMs and assess action potential duration, morphology, and contractile force.


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 = $42,853 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	2	4/14/2026	NON-COMPETING CONTINUATION	$42,853
														Subtotal = $42,853

Issue Date FY: 2025 ( Subtotal = $42,277 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	1	1/28/2025	NEW	$0
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	1	1/28/2025	NEW	$41,713
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cardiovascular Diseases Research	002	1	8/21/2025	NEW	$564
														Subtotal = $42,277

Grand Total All Awards = $85,130

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Investigating the role of SYNE1-Giant in Atrial Cardiomyopathy

Award Number: F31HL178278

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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