ERK signaling in arteriogenesis

项目摘要 正常和异常血管系统的发展和形成至关重要。 对正常生物学和疾病发病机制都有影响。血管动态平衡起着重要的作用 维持正常的血管和器官功能。我们和其他人最近的研究 实验室已经证实ERK1/2(细胞外受体激酶1和2)在 这些过程。然而，人们对这些激酶的作用和方式的了解非常有限。 这已经完成了。 我们建议确定ERK1和ERK2对动脉命运规范的相对贡献 和动脉形成，建立ERK活性调节的关键步骤，发现下游 信号通路，并破译ERK1和ERK2信号的功能效应。 在初步研究中，我们观察到缺失ERK1的小鼠的异常动脉生成 ERK2亚型缺失小鼠的异构体和异常血管生成。这些数据指向 这些激酶活性的意外特异性开启了选择性靶向的可能性 这两个过程。这样做的能力将具有巨大的临床意义。

Project Summary The development and formation of normal and abnormal vasculature is of critical importance to both normal biology and disease pathogenesis. Vascular homeostasis plays an important role in maintenance of normal vessel and organ function. Recent studies from our and other laboratories have established that ERK1/2 (extracellular receptor kinases 1 and 2) are critical to these processes. Yet there is a very limited understanding of what these kinases do and how this is accomplished. We propose to determine relative contributions of ERK1 vs. ERK2 to arterial fate specification and arteriogenesis, establish key steps in regulation of the ERK activity, discovery downstream signaling pathways, and decipher functional effects of ERK1 vs. ERK2 signaling. In preliminary studies we have observed abnormal arteriogenesis in mice missing the ERK1 isoform and abnormal angiogenesis in mice missing the ERK2 isoform. These data point to unexpected specificity of these kinases’ activity that open a possibility of selectively targeting these two processes. The ability to do so would be of tremendous clinical significance.