Fate-mapping of Cardiac Monocyte Recruitment and Specification

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Project Abstract Cardiovascular disease including myocardial infarction represents one of the leading causes of death worldwide. Despite currently available treatments, myocardial infarction remains a major index event which can lead to progression of heart failure. Current therapies focus on preventing the progression of adverse remodeling including development of fibrosis. However, little progress has been made in the development of treatments to prevent or reverse this remodeling. In recent years, it has been demonstrated that cardiac injury elicits an immense immune response involving the majority of known immune cell types. In recent years, it has also been demonstrated that the recruitment of monocytes leads to incredible diversity in macrophage populations with distinct expression profiles. Experiments in both mice and humans in numbers cardiovascular diseases has demonstrated this diversity. In this proposal, the PI aims to investigate how and when these diverse macrophage populations obtain their fate and investigate the potential of interferon signaling as a regulator of this diversification. The scientific goals of this award are to identify the spatiotemporal dynamics of macrophage recruitment and specification after cardiac injury. By the end of this award period, the PI aims to establish when monocytes entering the heart acquire their specific macrophage transcriptional profile as observed to be highly diverse in prior experiments. The PI will utilize new technologies including intravital 2-photon imaging and advanced computational biology techniques. The PI will also identify the role of interferon signaling in the specification of macrophage populations as well as in repair and inflammation after cardiac injury. This will be completed by modulating interferon signaling in recruited monocytes. At the end of this award period, the PI will have generated a better understanding of how the complex immune response to heart injury occurs. The career development goal of this proposal is to aid in the PI’s success in becoming an independent investigator. The PI has previously obtained a PhD in developmental biology and completed 3 years of postdoctoral training in cardiac immunology. The proposed 2-year mentored research time under this award will provide the PI with formal training in immunology, computational biology, and grant-writing. Additionally, the mentorship team and advisory committee will provide training and advice on technical skills, management skills, and making early career decisions. By completing this award period, the PI will have acquired the skills necessary to become a successful independent researcher.