Mixed Lineage Kinase 2 (MLK2) and vascular homeostasis

项目摘要 心血管疾病是该国导致死亡和残疾的主要原因之一，据估计，其成本 在美国超过3510亿美元。缺血诱导的血管生成在脑缺血后的恢复中起重要作用 许多血管疾病。血管内皮细胞在血管内稳态中发挥着更重要的作用，因为它 调节血管张力、血栓形成、白细胞运输、新陈代谢和血管生成。保持正常 内皮功能需要平衡许多生理和病理生理压力，如剪切， 缺氧和炎症。在介导细胞应激的途径中，应激激活的反应是 MAP激酶(MAPK)超家族成员，包括c-Jun氨基末端激酶(JNK)和p38MAPK。 JNK蛋白在发育过程中对侧支动脉的形成起重要作用。最近，我们展示了 提示神经JNK3在肢体缺血后血流恢复中起重要作用。在上游探测 MAPK信号级联的组成(MAP2K和MAP3K)，我们发现混合谱系Kinase 2 MAP3K和MAPK上游调节因子(Mlk2)在内皮细胞中表达，是正常细胞所必需的 出生后内皮细胞功能。事实上，mlk2缺陷的内皮细胞在血管生成方面表现出严重的缺陷。 以及内皮细胞的增殖和迁移。Mlk2也在血管内皮生长因子信号转导中发挥重要作用。 对于正常的内皮功能是必需的。Rna-seq数据表明mlk2缺陷的内皮细胞表现出 基础和血管内皮生长因子诱导的广泛保守的microRNA miR-146a上调，此前 与炎症有关。该miR-146a miRNA作用于野生型内皮细胞的模拟 概括了mlk2缺陷的广泛表型，包括增殖缺陷和血管内皮生长因子的缺陷。 发信号。使用这些策略，我们应该能够清楚地了解mlk2是如何影响的。 内皮功能和血管动态平衡。这些数据将是重要的，因为MLK抑制剂正在进行测试 在癌症领域，因为关于它们对心血管的影响的数据很少。此外， Mlk2是如何影响血管系统的，这是我们将要解决的一个巨大的知识缺口。

Project Summary Cardiovascular diseases are among the nation's leading causes of death and disability, with an estimated cost of more than $351 billion in the USA. Ischemia-induced angiogenesis plays an important role in the recovery of many vascular diseases. The endothelium plays an even more important role in vascular homeostasis as it regulates vascular tone, thrombosis, leukocyte trafficking, metabolism, and angiogenesis. Maintaining normal endothelial function requires balancing numerous physiological and pathophysiological stresses such as shear, hypoxia, and inflammation. Among the pathways mediating cellular stress, responses are the stress-activated members of the MAP kinase (MAPK) superfamily, which includes c-Jun N-terminal kinase (JNK) and p38 MAPK. JNK protein plays an important role in collateral artery formation during development. Recently, we have shown that neural JNK3 plays a significant role in blood flow recovery after hindlimb ischemia. In probing upstream components of the MAPK signaling cascade (MAP2K and MAP3K), we found that Mixed Lineage Kinase 2 (MLK2), a MAP3K and upstream regulator of MAPK, is expressed in endothelium and required for normal postnatal endothelial function. In fact, MLK2-deficient endothelial cells exhibit profound defects in angiogenesis as well as endothelial proliferation and migration. MLK2 also plays a significant role in VEGF signaling, which is required for proper endothelium function. RNA-seq data indicates that MLK2-deficient endothelial cells exhibit both basal and VEGF- induced upregulation of a broadly conserved microRNA, miR-146a, that has previously been linked to inflammation. Mimics of this miR-146a miRNA administered to wild-type endothelial cells recapitulate a broad spectrum of the MLK2-deficient phenotype, including defects in proliferation and VEGF signaling. Using these strategies, we should be able to develop a clear picture of how MLK2 influences endothelial function and vascular homeostasis. These data will be important as MLK inhibitors are being tested in the cancer field since very little data is understood regarding their cardiovascular consequences. Moreover, how Mlk2 influences the vasculature is a large gap in knowledge that we will address.