Characterising novel mediators of vascular calcification.

表征血管钙化的新型介质。

• 批准号: BB/F023928/1
• 负责人: Vicky MacRae
• 金额: $ 120.01万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF023928%2F1
• 关键词: Characterising; novel; mediators; vascular; calcification.

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.

据世界卫生组织 (WHO) 统计，每年估计有 1700 万人死于心血管疾病，特别是心脏病和中风。心血管疾病发生的一个重要危险因素是血管钙化。血管钙化过程与骨骼矿化过程有许多相似之处，都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。最近显示，一个自我调节蛋白家族可以改变激素成纤维细胞生长因子 23 (FGF23) 的循环水平，与 FGF23 本身一起对骨骼矿化产生直接影响。这些蛋白质包括 DMP1（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）。该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。最初，将确定血管平滑肌细胞 (VSMC) 钙化过程中 FGF23、PHEX、DMP1 和 MEPE 的基因和蛋白表达模式（血管钙化模型），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小鼠模型中得到证实。基因敲除和过度表达研究将研究 FGF23、PHEX、DMP1 和 MEPE 在 VSMC 和成骨细胞中的功能。为了发现其基础机制，我们将研究血管钙化过程中 FGF23、PHEX、DMP1 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，还将对 FGF23、PHEX、DMP1 和 MEPE 的新型抑制剂或诱导剂进行研究。最后，将对血管钙化期间改变的所有基因和 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。

项目成果

End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.

• DOI: 10.1002/jcp.25935
• 发表时间: 2017-11
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Cui L;Rashdan NA;Zhu D;Milne EM;Ajuh P;Milne G;Helfrich MH;Lim K;Prasad S;Lerman DA;Vesey AT;Dweck MR;Jenkins WS;Newby DE;Farquharson C;Macrae VE
• 通讯作者: Macrae VE

Isolation and Characterization of Primary Rat Valve Interstitial Cells: A New Model to Study Aortic Valve Calcification.

• DOI: 10.3791/56126
• 发表时间: 2017-11-20
• 期刊: Journal of visualized experiments : JoVE
• 作者: Lin C;Zhu D;Markby G;Corcoran BM;Farquharson C;Macrae VE
• 通讯作者: Macrae VE

Mineralisation of collagen rich soft tissues and osteocyte lacunae in Enpp1(-/-) mice.

• DOI: 10.1016/j.bone.2014.09.016
• 发表时间: 2014-12
• 期刊: BONE
• 影响因子: 4.1
• 作者: Hajjawi, Mark O. R.;MacRae, Vicky E.;Huesa, Carmen;Boyde, Alan;Millan, Jose Luis;Arnett, Timothy R.;Orriss, Isabel R.
• 通讯作者: Orriss, Isabel R.

Pharmacological inhibition of PHOSPHO1 suppresses vascular smooth muscle cell calcification.

• DOI: 10.1002/jbmr.1733
• 发表时间: 2013-01
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Kiffer-Moreira, Tina;Yadav, Manisha C.;Zhu, Dongxing;Narisawa, Sonoko;Sheen, Campbell;Stec, Boguslaw;Cosford, Nicholas D.;Dahl, Russell;Farquharson, Colin;Hoylaerts, Marc F.;MacRae, Vicky E.;Millan, Jose Luis
• 通讯作者: Millan, Jose Luis

Deficiency of the bone mineralization inhibitor NPP1 protects mice against obesity and diabetes.

• DOI: 10.1242/dmm.017905
• 发表时间: 2014-12
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Huesa C;Zhu D;Glover JD;Ferron M;Karsenty G;Milne EM;Millan JL;Ahmed SF;Farquharson C;Morton NM;MacRae VE
• 通讯作者: MacRae VE