"Leukemia inhibitory factor" as novel mediator of vascular calcification

“白血病抑制因子”作为血管钙化的新型介质

• 批准号: 395858096
• 负责人: Dr. Jakob Völkl
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/395858096?language=en
• 关键词: Leukemia; inhibitory; factor; novel; mediator

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.

中膜血管钙化（VC）发生在衰老、糖尿病和慢性肾衰竭期间。血管钙化已被认为是心血管死亡的重要危险因素。血管钙化是一个由血管平滑肌细胞介导的主动过程。这个过程是由一个复杂的信号级联网络调节的。到目前为止，还没有可用的治疗方法。本研究旨在探讨一种新发现的具有重要治疗意义的VC介导因子-白血病抑制因子（LIF）及其信号网络在血管钙化过程中的作用。VC动物模型血浆中的蛋白质组学实验鉴定了可溶性LIF受体的显著下调，其可能充当内源性LIF拮抗剂。初步实验表明，LIF在VC期间表达增加，并强烈增强VC。LIF的沉默可以减弱血管平滑肌细胞的成骨重建。本研究将探讨LIF在VC中的确切功能。此外，将确定介导LIF在血管系统中的作用的信号网络。进一步的实验将研究是否LIF或其信号通路的阻断可能会减少VC作为治疗靶点。这些研究可以确定一个新的血管钙化及其细胞内途径的关键调节剂。LIF及其可溶性受体作为拮抗剂可能是一个容易获得的靶点。因此，这些观察结果对于VC的临床治疗具有直接的翻译重要性。