Project Summary/abstract Surgical percutaneous coronary intervention is an effective reperfusion treatment for reducing acute myocardial ischemic injury and limiting infarct size. However, the process of reperfusion can itself induce cardiac cell damage (known as ischemia-reperfusion injury). The search for a therapeutic target that can salvage ischemic cardiac myocytes and prevent cell death from ischemia-reperfusion injury remains a daunting challenge. Insulin-like growth factor 2 receptor (IGF2R) exerts multiple functions and has been implicated in cardiovascular disease. Our preliminary experiments showed that the translocation of IGF2R to the plasma membrane was increased in response to ischemia-reperfusion injury, while cell death was attenuated by inhibition of IGF2R. In order to further investigate IGF2R as a new, effective target for cardioprotection, we propose three Specific Aims to define the pathological role of IGF2R in myocardial ischemia-reperfusion injury and to provide proof-of-concept for applications of an IGF2R antagonist in preclinical studies. Aim 1: Experiments are designed to reveal the molecular mechanism of IGF2R redistribution in cardiomyocytes after ischemia-reperfusion injury. Interaction between trafficking proteins and IGF2R will be investigated in this study. Aim-2: Experiments are designed to assess cell signaling transduced by IGF2R in cardiomyocytes. The expression of IGF2R will be modified using inducible CRISPR-based approaches to determine whether IGF2R acts as a critical receptor mediating multiple cell death pathways (such as apoptosis and pyroptosis) in response to ischemia-reperfusion injury. Aim-3: The therapeutic effects of an IGF2R aptamer (antagonist) will be evaluated in mouse and porcine studies. Transgenic mice will be used to determine whether the mechanism of IGF2R inhibition is dependent on other insulin-like growth factor receptors. The safety of using an IGF2R aptamer will be tested in porcine models. In conclusion, the experiments outlined in this proposal are designed to establish a new paradigm for inhibition of IGF2R using an aptamer, and will provide a new cardioprotective strategy to reduce ischemia-reperfusion injury during heart surgeries.