Inhibition of Wnt signaling in monocytes and its possible role for healing in acute myocardial infarction.

心肌梗死引起无菌免疫反应，影响愈合和随后的心室功能。单核细胞在炎症过程中起关键作用。虽然近年来我们对单核细胞在心脏损伤后的全身活化的了解已经大大增加，但对心脏微环境对这些积累的白细胞的影响知之甚少。我们已经确定了Wnt信号在单核细胞局部激活中的新作用，并描述了心肌细胞分泌的Wnt抑制因子1 （WIF1）是这一过程的关键调节剂。我们现在的目标是(1)评估全身给药重组WIF1和(2)单核细胞特异性抑制非典型Wnt信号传导对心肌梗死后愈合的影响。我们还旨在进一步阐明心肌细胞分泌的Wnt蛋白对单核细胞积累和心脏愈合的影响。为此，我们将分析(3)小分子介导的Wnt分泌抑制和(4)诱导心肌细胞特异性缺失Evi的转基因小鼠，Evi是Wnt分子分泌所必需的受体。综上所述，这些研究的目的是促进我们对心脏损伤后Wnt信号的理解，并确定调节髓细胞活化以改善心肌梗死后愈合的新方法。

Myocardial infarction elicits a sterile immune response that impacts healing and subsequent ventricular function. Monocytes are key players in this inflammatory process. While our understanding of systemic activation of monocytes following cardiac injury has substantially grown in recent years, little is known about the impact of the cardiac microenvironment on these accumulating leukocytes. We have identified a novel role for Wnt signaling in local activation of monocytes and describe cardiomyocyte-secreted Wnt-Inhibitory Factor 1 (WIF1) as a crucial modulator of this process. We now aim to (1) evaluate the effect of systemic administration of recombinant WIF1 and (2) monocyte-specific inhibition of non-canonical Wnt signaling on healing after myocardial infarction. We also aim to further elucidate the impact of Wnt proteins secreted from cardiomyocytes on accumulating monocytes and cardiac healing. To this end, we will analyze (3) small molecule mediated inhibition of Wnt secretion and (4) transgenic mice with an inducible cardiomyocyte-specific deletion of Evi, a receptor essential for the secretion of Wnt molecules. Taken together, the goal of these investigations is to advance our understanding of Wnt signaling following cardiac injury and to identify novel approaches for the modulation of myeloid cell activation to improve healing after myocardial infarction.