Research Project
10462471
PROJECT SUMMARY A growing body of evidence suggests significant roles for myeloid cells in cardiac physiology. For one, these leukocytes have been reported to partake in the maintenance of functional and structural homeostasis. Additionally, after injury, myeloid cell processes can enormously influence short- and long-term remodeling and repair outcomes. Given these paramount roles, a lot of recent work has focused on identifying and examining exactly how these leukocytes are regulated. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is known to critically govern many cell processes including migration, proliferation and survival. Interestingly, recent reports suggest that EGFR regulates macrophage activation and function, however it is currently unknown if, and how EGFR might influence myeloid cell responses to ischemic injury. As such, we have generated myeloid cell-specific EGFR knockout mice (EGFR mylKO) to determine the impact of such deletion on acute cardiac injury outcomes. Following baseline analysis, EGFR mylKO mice exhibited increased cardiomyocyte size, and fetal gene expression compared to aged matched floxed EGFR (EGFRf/f) controls. To assess differences in post-injury inflammation, we subjected EGFR mylKO and controls to myocardial infarction (MI). Within 1 week post-MI, EGFR mylKO mice displayed worse systolic function, enhanced LV dilation, and increased immune cell presence in the heart when compared to controls. These phenotypes lead us to question how myeloid cell-specific EGFR invokes physiological changes in the steady state and injured heart. We hypothesize that myeloid cell-specific EGFR is crucial in regulating post-injury inflammation and cardiac remodeling outcomes. We will address our research questions by further examining the impact of myeloid cell EGFR deletion on cardiac structure/function (Aim 1) and determining the role of myeloid cell EGFR deletion on cardiac myeloid cell dynamics (Aim 2). Conclusion of this work will aid in our understanding of the mechanisms which contribute in the transition from injury to heart failure.
