"Leukemia inhibitory factor" as novel mediator of vascular calcification

内侧血管钙化（VC）发生于衰老、糖尿病和慢性肾衰竭。血管钙化已被认为是心血管死亡的一个重要危险因素。血管钙化是一个由血管平滑肌细胞介导的活跃过程。这个过程是由一个复杂的信号级联网络调节的。直到现在，还没有有效的治疗方法。本项目旨在研究一种新发现的VC介质，这可能是主要的治疗相关性。本研究旨在探讨白血病抑制因子（Leukemia inhibitory factor， LIF）及其信号网络在血管钙化过程中的作用。VC动物模型血浆蛋白质组学实验发现可溶性liff受体显著下调，该受体可能是内源性liff拮抗剂。初步实验表明，在VC过程中，LIF表达增加，并强烈增强VC。抑制LIF可抑制血管平滑肌细胞的成骨重塑。本研究将探讨在VC过程中LIF的确切功能。此外，将确定介导LIF在脉管系统中的作用的信号网络。进一步的实验将研究阻断LIF或其信号通路是否可以降低VC作为治疗靶点。这些研究可以确定一种新的血管钙化及其细胞内通路的关键调节因子。LIF及其作为拮抗剂的可溶性受体可能是药理学上容易获得的靶点。因此，这些观察结果对VC的临床治疗具有直接的翻译意义。

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.