Characterizing SynNotch receptors to drive vascularization for improved cardiac regeneration.

Project Description

Principal Investigator: Dr. Chris Chen

Myocardial infarction occurs when there is a lack of blood flow to the heart, resulting in a loss of nutrients and oxygen to the tissue. Without oxygen, the cardiac tissue undergoes necrosis and cardiac remodeling occurs. During this process, cardiac fibrosis takes place, and necrotic tissues are replaced by fibrotic scars. While the scar tissues maintain the structural integrity of the heart, it is often associated with increased tissue stiffness, arrhythmias, heart failure, and an overall unfavorable prognosis.

A longstanding goal of the Cell-MET program includes engineering a cardiac patch that can be grafted onto scar tissues to assist with heart function. To do so, the patch must be vascularized to effectively deliver nutrients and oxygen to the engineered tissue. Additionally, the presence of a vascular network in the patch can act as a seed to promote rapid anastomosis with the host vasculature, encouraging proper blood circulation.

To study tissue vascularization, the Chen lab is currently developing chimeric SynNotch receptors to enhance vascular barrier function. In these receptors, the extracellular domain is replaced by a fluorescein-binding antibody fragment (anti-FITC scFv). This modification allows us to activate Notch signaling using substrate-immobilized FITC instead of a native Notch ligand, which would activate multiple native Notch receptor isoforms in the cells. Additionally, mutations have been introduced into these receptors to decouple canonical transcriptional Notch signaling from barrier-enhancing cortical Notch signaling. This allows us to control specific signaling pathways while avoiding undesirable secondary effects.

Together with Jessica Teo, a postdoctoral researcher in the Chen lab, the REU student will help test the temporal dynamics of SynNotch receptors as well as identify receptors that enhance vascular barrier function from those that do not in human endothelial cells.

Mentor

Jessica Teo