Role of the LINC Complex in Heart Rhythm Disorders
Description: This proposal will test the hypothesis that nucleocytoplasmic coupling plays a key role in the pathogenesis of atrial fibrillation (AF) and sinus node dysfunction (SND), the two most common dysrhythmias. Recent findings from large genome-wide association studies and from individual patients with Mendelian disorders have begun to shed light on these questions by demonstrating a causal association of atrial fibrillation with genes that encode the Linker of Nucleoskeleton and Cytoskeleton (LINC) Complex: SYNE1, SYNE2 and SUN1. Additionally our research team has identified a patient with a mutation in SYNE1 that led to early-onset AF and eventually atrial standstill. To test whether compromise of LINC function through mutation, aging, or chronic stretch disrupts nuclear structure, contractile function, and gene expression, leads to atrial pathogenesis, we have necessarily assembled a complementary research team with deep expertise in cardiac electrophysiology, gene regulation, and disease modeling using tissue engineering. Successful completion of this proposal will open a new field of investigation for understanding how aging, chronic mechanical force, and altered genome organization and function are related to atrial pathology and may ultimately lead to new approaches to modify the course of this increasingly common disease.
Funder: American Heart Association
Amount: $750,000
Funding type: research
Funder scheme: Collaborative Sciences Award
Start date: 2024-07-01
End date: 2027-06-30
Investigators: Vasanth Vedantham, Vasanth Vedantham, Matthew Kutys, Arun Padmanabhan
Institution: The Regents of the University of California, San Francisco
Funded outputs count: 0
Funder award ID: 24CSA1252970
OpenAlex ID: G757571793