The Role of Myeloid Cell-Specific Epidermal Growth Factor Receptor in Cardiac Pathophysiology

项目摘要 越来越多的证据表明骨髓细胞在心脏生理学中的重要作用。首先，这些 据报道，白细胞参与维持功能和结构稳态。 此外，损伤后，骨髓细胞过程可以极大地影响短期和长期的重塑， 修复结果。鉴于这些重要作用，最近的许多工作都集中在确定和审查 这些白细胞是如何被调节的表皮生长因子受体（EGFR）是一种酪氨酸受体， 已知其关键地控制许多细胞过程，包括迁移、增殖和存活。 有趣的是，最近的报道表明，EGFR调节巨噬细胞的活化和功能，然而， 目前尚不清楚EGFR是否以及如何影响骨髓细胞对缺血性损伤的反应。因此我们 已经产生了骨髓细胞特异性EGFR敲除小鼠（EGFR mylKO），以确定这种 删除急性心脏损伤结局。基线分析后，EGFR mylKO小鼠表现出增加的 与年龄匹配的floxed EGFR（EGFRf/f）对照相比，心肌细胞大小和胎儿基因表达。到 为了评估损伤后炎症的差异，我们将EGFR mylKO和对照组进行了心肌损伤， 心肌梗死（MI）。在MI后1周内，EGFR mylKO小鼠显示出更差的收缩功能，增强的LV 扩张和增加的免疫细胞存在的心脏相比，控制。这些表型导致 我们质疑骨髓细胞特异性EGFR如何在稳态和损伤状态下引起生理变化， 心我们假设髓样细胞特异性EGFR在调节损伤后炎症中起关键作用， 心脏重塑结果。我们将通过进一步研究 髓样细胞EGFR缺失对心脏结构/功能的影响（Aim 1）和确定髓样细胞EGFR的作用 EGFR缺失对心肌髓样细胞动力学的影响（目的2）。这项工作的结论将有助于我们理解 从损伤到心力衰竭转变的机制。

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.