Myocarditis is a significant contributor to heart-related malignancies and is responsible for ~10% of sudden deaths following cardiac arrest in young adults. Inflammation most often arises as a result of viral infection mediated by the pro-inflammatory cytokines secreted upon detection of the virus. Type-I interferon (IFN-I) is one of these cytokines and a central player in eliciting an antiviral response and through its immunomodulatory properties. Despite their reliance on IFN-signaling to fight virus, cardiomyocytes are also highly sensitive to the damage inflicted by inflammation because of their inability to regenerate. Therefore, we hypothesize that cardiomyocytes possess a unique IFN-I response which is tightly regulated and tuned to antagonize virus infection while avoiding excess inflammation. This hypothesis is based on the fact that other specialized cell types are known to have unique transcriptional responses to IFN-I and there is also evidence suggesting that this applies to cardiomyocytes as well. Furthermore, our group has recently shown that IFN-I is implicated in the differentiation of human induced pluripotent stem cells (iPSCs) to cardiomyocytes, which has prompted renewed interest in the relationship between cardiomyocyte biology and this cytokine. Furthermore, the importance of understanding how cardiomyocytes respond to infection and inflammation has been underscored by the increasing number of COVID-19 related cases of various cardiomyopathies.In this proposal, we wish to thoroughly characterize the interplay between IFN-I and cardiac function and development through transcriptional and developmental studies. We have built a single-cell CRISPR-screen sequencing platform that allows for rapid and comprehensive genetic screens that we propose to use for a characterization the IFN-I response of cardiomyocytes and delineate the role of each signaling component in this response to identify unique aspects of cardiomyocyte IFN-I signaling. Furthermore, we propose to investigate the involvement of IFN-I signaling in the differentiation of iPSCs to cardiomyocytes and how loss of IFN-I signaling impacts functionality and response to infection with SARS-CoV-2 in cardiomyocytes. Together, these aims will provide valuable insight to how IFN-I signaling impacts cardiomyocyte function which may lead to novel methods of treatment and/or prevention of myocarditis.
|Effective start/end date||1/04/21 → 31/03/23|
- American Heart Association: $63,000.00