Programmable RNA sensing system for precise targeting of cardiac fibroblasts
Description: Heart failure remains a leading global cause of morbidity and mortality, frequently driven by excessive cardiac fibrosis following myocardial infarction (MI). Cardiac fibroblasts (CFs) are central to this pathological process, producing extracellular matrix proteins that promote scar formation, increase myocardial stiffness, and drive adverse remodeling. Current strategies aimed at targeting CFs, including fibrotic cell depletion and lineage reprogramming, are limited by inefficiency and poor specificity of existing gene delivery tools. To overcome these barriers, we propose the development of a novel RNA sensor platform that exploits Adenosine Deaminases Acting on RNA (ADAR) technology, which has not yet been studied in the field of cardiac fibrosis and cellular reprogramming. The Central Hypothesis of this proposal is that an ADAR-based system can be engineered as RNA sensors that selectively target CF-specific RNA transcripts, thereby enabling controlled actuator expression for antifibrotic or fibrosis-reversing interventions. We will pursue this hypothesis through two Specific Aims. In Aim 1, we will engineer an ADAR-based RNA sensor capable of detecting CF subtype-specific markers, such as Fibroblast Activation Protein (Fap), to enable precise antifibrotic responses via cell-ablation effectors. In parallel, in Aim-2, we will integrate the RNA-sensing system with CRISPR activation technology to induce lineage reprogramming in Periostin-expressing CFs by activating cardiogenic transcription factors. This will facilitate the conversion of CFs into cardiomyocytes, thereby reducing fibrosis and restoring cardiac function. By leveraging single-cell RNA sequencing to identify subtype-specific CF markers, this strategy has the potential to establish a new therapeutic paradigm for reversing fibrosis and improving cardiac repair in heart failure.
Funder: American Heart Association
Amount: $70,680
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2026-01-01
End date: 2027-12-31
Investigators: SUCHANDRIMA DUTTA, SUCHANDRIMA DUTTA
Institution: University of Cincinnati
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Funded outputs count: 1
Funder award ID: 26PRE1565814
OpenAlex ID: G596277066