# Role of Nucleoside-Diphosphate Kinase Signaling in Atrial Fibrillation

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $524,630

## Abstract

PROJECT SUMMARY / ABSTRACT
Atrial fibrillation (AF), the most common arrhythmia, is associated with high morbidity and mortality, but
remains difficult to treat due to an incomplete understanding of underlying mechanisms. Emerging evidence
suggests that nucleoside diphosphate kinases (NDPKs) play an important role in the heart by being able to
elevate cAMP levels in a G-protein receptor-independent manner. Our pilot data suggest that increased levels
of NDPK-B and NDPK-C isoforms in patients with persistent (chronic) AF are associated with elevated cAMP
levels, abnormal sarcoplasmic reticulum Ca2+ releases, ectopic (triggered) activity and inducible AF. The long-
term goal of this project is to dissect the molecular and cellular basis of NDPK-dependent arrhythmia
mechanisms in AF. The central hypothesis is that enhanced NDPK-B and -C levels promote AF by enhancing
cAMP levels in the RyR2 microdomain, resulting in aberrant intracellular Ca2+ signaling that creates a substrate
for AF initiation, maintenance, and progression. Three specific aims will be pursued: 1) Determine whether
increased NDPK expression is both necessary and sufficient to promote spontaneous AF, 2) Assess whether
elevated NDPK levels cause cAMP-dependent SR Ca2+ leak via RyR2, and 3) Determine the role of Ankrd1
within the RyR2-NDPK signaling complex. These studies will be performed in atrial myocytes from patients
with AF, a dog model of AF, and various atrial-selective genetic mouse models of AF. Novel targeted cAMP
FRET sensors and atrial-selective adeno-associated virus (AAV9)-mediated gene therapy will be utilized to
resolve the pro-arrhythmic roles of NDPK-B/C and cAMP within specific cellular microdomains. These studies
are expected to establish whether and how NDPK isoforms contributes to AF development and serve as a
platform for the validation of NDPKs as novel druggable target for the prevention or treatment of AF.

## Key facts

- **NIH application ID:** 10778565
- **Project number:** 5R01HL160992-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Xander H.T. Wehrens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $524,630
- **Award type:** 5
- **Project period:** 2023-02-06 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10778565

## Citation

> US National Institutes of Health, RePORTER application 10778565, Role of Nucleoside-Diphosphate Kinase Signaling in Atrial Fibrillation (5R01HL160992-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10778565. Licensed CC0.

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