Mechanisms to promote ETV2-mediated reprogramming for ischemic heart disease
Description: This proposal aims to enhance the reprogramming efficiency of ETV2, a pioneer factor that can reprogram fibroblasts into endothelial cells, to treat ischemic heart disease (IHD) by promoting revascularization. IHD affects over 200 million people worldwide, often leading to heart attacks due to restricted blood flow. Current treatments like coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) have limitations, including graft failure or restenosis which leads to repeated interventions. The innovative approach proposed here focuses on using ETV2 to form new blood vessels in the ischemic regions of the heart, potentially offering a less invasive and more effective treatment. The primary challenge in using ETV2 is its low reprogramming efficiency and the unknown mechanisms behind its function in vivo. This proposal aims to overcome these hurdles by identifying transcription cofactors that can work with ETV2 to enhance its reprogramming efficiency. The central hypothesis is that ETV2 reprograms cardiac fibroblasts to endothelial cells in the heart, which can be further enhanced by specific transcriptional cofactors. The research has two main goals: Aim1: Identify mechanisms underlying ETV2- and SALL4-mediated reprogramming in embryonic and adult fibroblasts in vitro. ETV2 and SALL4 will be overexpressed in different types of mouse fibroblasts using retrovirus. scRNA-seq, ATAC-seq and CUT&RUN analyses followed by gain- and lose-of-function experiments will identify the mechanisms and pathways involved. Aim2: Define the mechanisms of ETV2-mediated reprogramming in promoting revascularization and treating IHD in vivo. Fibroblast lineage-tracing mice will be used to track the reprogramming efficiency and the fate of reprogrammed fibroblasts in vivo. Echocardiography will be used to determine cardiac function improvements. Spatial transcriptomics will be used to analyze the cell-to-cell interaction and integration of reprogrammed cells into the system. This will evaluate the aptness of ETV2 and SALL4 in IHD treatment and in vivo reprogramming mechanism. Successful completion of the project could offer a new treatment option for IHD that can be employed alone or with other treatments. By improving the efficiency of ETV2-mediated reprogramming and understanding its mechanisms, it can also have broader implications for traeting other ischemic conditions as well as direct reprogramming mediated by other master regulators.
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: Young Geun Choi, Young Geun Choi
Institution: Regents of the University of Minnesota - Twin Cities
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 0
Funder award ID: 26PRE1564171
OpenAlex ID: G8335755321