"Leukemia inhibitory factor" as novel mediator of vascular calcification

中层血管钙化(VC)发生在衰老、糖尿病和慢性肾功能衰竭期间。血管钙化已被认为是心血管死亡的重要危险因素。血管钙化是由血管平滑肌细胞介导的一个活跃的过程。这一过程由一个复杂的信令级联网络来调节。到目前为止，还没有可用的治疗方法。本研究旨在研究一种可能具有重要治疗意义的新发现的VC介质。本研究的目的是探讨白血病抑制因子(LIF)及其信号网络在血管钙化中的作用。在VC动物模型血浆中的蛋白质组学实验证实，作为内源性LIF拮抗剂的可溶性LIF受体显著下调。初步实验表明，LIF在VC中表达增加，并强烈增强VC。沉默LIF可抑制血管平滑肌细胞的成骨重塑。本研究将探讨LIF在VC中的确切作用。此外，还将确定介导LIF在血管系统中的作用的信号网络。进一步的实验将探讨阻断LIF或其信号通路是否可以减少作为治疗靶点的VC。这些研究可以确定一种新的血管钙化关键调节因子及其细胞内途径。LIF及其可溶性受体作为拮抗剂，可作为药物易达性靶点。因此，这些观察结果对VC的临床治疗具有直接的翻译重要性。

Medial vascular calcification (VC) occurs during aging, diabetes and chronic renal failure. The calcification of the vasculature has been recognized as an important risk factor for cardiovascular mortality. Vascular calcification is an active process mediated by vascular smooth muscle cells. This process is regulated by a complex network of signaling cascades. Until now, no therapeutic treatment is available. This project aims to investigate a newly identified mediator of VC, which could be of major therapeutic relevance.Aim of this study is to investigate the role of the Leukemia inhibitory factor (LIF) and its signaling network during vascular calcification. Proteomic experiments in plasma of VC animal model identified a dramatic downregulation of the soluble LIF-receptor, which presumably acts as endogenous LIF-antagonist. Preliminary experiments indicate, that LIF is increasingly expressed during VC and strongly augments VC. Silencing of LIF can blunt osteogenic remodeling of vascular smooth muscle cells. This study will investigate the precise function of LIF during VC. Furthermore, the signaling networks mediating the effects of LIF in the vasculature will be identified. Further experiments will investigate whether blockade of LIF or its signaling pathways may reduce VC as therapeutic target.These studies can identify a novel critical regulator of vascular calcification and its intracellular pathways. LIF and its soluble receptor as antagonist could be pharmacologically easily accessible targets. These observations can therefore be of direct translational importance for the clinical treatment of VC.