Sex-dependent regulation of cardiac cAMP, ECC, and arrhythmia by phosphodiesterases
- Institution
- UNIVERSITY OF CALIFORNIA LOS ANGELES, CA
- Principal investigator
- Yang Kevin Xiang
- Funding
- $650K
- Duration
- 2025–2029
Moonbase score
Still being scored
Abstract
Abstract Autonomic dysregulation and aberrant intracellular signaling are hallmarks of both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Cyclic AMP (cAMP) is a key second messenger that transduces extracellular autonomic adrenergic signals to control downstream contractility and electrophysiology on a beat-to-beat basis. Aberrant cAMP signaling likely plays an important role in Ca2+ mishandling, contractile dysfunction, and arrhythmias in HF. cAMP is highly compartmentalized by b-adrenoceptor (b-AR)-induced cAMP synthesis and phosphodiesterase (PDE)-mediated degradation. The overall goal of this project is to determine the differential role of heterogeneous PDE4D signaling in contributing to dysfunctional excitation-contraction coupling (ECC) and arrhythmias in HFpEF vs. HFrEF in a sex-dependent manner. The main hypothesis that will be tested in this project is that either too much or too little PDE activity in cardiomyocytes can impair ECC and promote arrhythmias, and that underlying sex differences in PDE activity modulate sex-dependent responses. Using a novel integrated whole-heart imaging approach combined with single cell analysis and detailed subcellular signaling studies and FRET-based reporters, we will comprehensively determine signaling responses and functional outcomes from the molecular, cellular, to whole- heart level, which may ultimately suggest more personalized treatment strategies for men and women with HF.
Research team
- Crystal May RipplingerPI
- Yang Kevin XiangPI
LOADING MOONBASE SCORE
Questions for UNIVERSITY OF CALIFORNIA LOS ANGELES
Answered by the team behind this research.
No questions yet. Sign in to ask the first one
Related grants
Same researchers, same institution, same topic, scored first.
- NIH · University of California Los AngelesNot yet scored
Sex differences in cardiac autonomic remodeling after myocardial infarction
Crystal May Ripplinger · $705K · 2023–2027
- NIH · University of California at DavisNot yet scored
Phosphodiesterases govern nuclear cAMP signaling for gene expression
Yang Kevin Xiang · $621K · 2023–2028
- NIH · University of California at DavisNot yet scored
Phosphodiesterases govern nuclear cAMP signaling for gene expression
Yang Kevin Xiang · $95K · 2023–2028