Olivia Zaleski

Cardiomyocytes undergo extensive structural, metabolic, and transcriptional remodeling during postnatal maturation to establish and maintain cardiac function. In heart failure (HF), this mature state is partially reversed through reactivation of fetal gene expression programs, contributing to disease progression. RNA processing is a key regulator of both cardiac development and HF, yet the mechanisms governing these transitions remain poorly understood. My research will focus on developing splice-switching antisense oligonucleotides (ASOs) with enhanced myocardial uptake to selectively redirect endogenous RNA processing in cardiomyocytes. These ASOs will be designed to modulate alternative splicing and transcript fate by sterically blocking critical splice-regulatory elements within the pre-mRNAs of RNA processing factors implicated in HF. Using these ASOs in HF models, I will define how these RNA processing factors regulate pathological gene expression programs that drive HF progression. Ultimately, this work will provide mechanistic insight into cardiac gene regulation and inform the development of chemically engineered RNA therapeutics for HF.