Characterising novel mediators of vascular calcification.

据世界卫生组织（WHO）估计，每年有1700万人死于心血管疾病，特别是心脏病发作和中风。血管钙化是心血管疾病发展的一个重要危险因素。血管钙化的过程与骨骼矿化的过程有许多相似之处，并且涉及磷酸钙矿物质在动脉、心脏瓣膜和心肌中的沉积。血管钙化具有严重的临床后果，然而，血管钙化的介质和机制尚未完全阐明。一个改变激素成纤维细胞生长因子-23（FGF 23）循环水平的自我调节蛋白家族最近被证明对骨骼矿化沿着FGF 23本身产生直接影响。这些蛋白质包括DMP 1（牙本质基质蛋白1）、PHEX（X染色体上的磷酸调节中性内肽酶）和MEPE（基质细胞外磷酸糖蛋白）。这项奖学金提案将研究这些新发现的骨骼矿化介质是否也形成血管钙化的调节网络。首先，将在血管平滑肌细胞（VSMC）钙化（血管钙化模型）期间确定FGF 23、PHEX、DMP 1和MEPE的基因和蛋白质表达模式，并与成骨细胞（骨骼矿化模型）进行比较。这些观察结果将在血管钙化的小鼠模型中得到证实。基因敲减和过表达研究将研究FGF 23、PHEX、DMP 1和MEPE在VSMC和成骨细胞中的功能。为了发现基础机制，将研究血管钙化过程中FGF 23、PHEX、DMP 1和MEPE对关键信号通路的调节。为了评估针对血管钙化的潜在治疗策略，还将进行FGF 23、PHEX和DMP 1以及MEPE的新型抑制剂或诱导剂的研究。最后，将对血管钙化过程中改变的所有基因和microRNA（可以调节基因表达的蛋白质量）进行大规模分析。这将确定血管钙化的新介质和潜在的治疗靶点。

According to the World Health Organisation (WHO), an estimated 17 million people die each year of cardiovascular diseases, particularly heart attacks and strokes. A significant risk factor in the development of cardiovascular disease isVascular calcification. The process of vascular calcification shares many similarities with that of skeletal mineralisation, and involves the deposition of calcium phosphate mineral in arteries, heart valves, and cardiac muscle. Vascular calcification has severe clinical consequences, however, the mediators and mechanisms of vascular calcification have yet to be fully elucidated. A family of self-regulating proteins which alter the circulating levels of the hormone fibroblastic growth factor-23 (FGF23) have been recently shown to exert direct effects on skeletal mineralisation, along with FGF23 itself. These proteins include DMP1 (dentin matrix protein 1), PHEX (phosphate regulating neutral endopeptidase on chromosome X) and MEPE (matrix extracellular phosphoglycoprotein). This fellowship proposal will examine whether these newly discovered mediators of skeletal mineralisation also form a regulatory network in vascular calcification. Initially, the gene and protein expression patterns of FGF23, PHEX, DMP1 and MEPE will be determined during the calcification of vascular smooth muscle cells (VSMCs) (vascular calcification model) and compared to osteoblasts (skeletal mineralisation model). These observations will be confirmed in mice models of vascular calcification. Gene knockdown and over expression studies will investigate the function of FGF23, PHEX, DMP1 and MEPE in VSMCs and osteobasts. To discover the underpinning mechanisms, the regulation of key signaling pathways by FGF23, PHEX, DMP1 and MEPE during vascular calcification will be studied. To assess potential therapeuric strategies against vascular calcification, the study of novel inhibitors or inducers of FGF23, PHEX and DMP1 and MEPE will also be undertaken. Finally, a large scale analysis of all the genes and microRNAs (which can regulate the amount of protein expressed by the genes) altered during vascular calcification will be undertaken. This will identify new mediators of vascular calcification and potential therapeutic targets.