How do sex hormones regulate the function of arteries and valves?

心脏病和中风影响大约三分之一的人，部分原因是动脉和瓣膜因钙沉积而变硬（1）。然而，这种情况是如何发生的，以及为什么心脏病在男性中更普遍还不完全清楚。我们的研究小组最近的研究（2，3）表明，睾酮导致动脉壁中正常存在的肌肉细胞部分转化为骨细胞，并沉积类似于骨骼中发现的物质的钙盐。总的结果是动脉壁增厚和硬化，心脏病的风险更高。本项目将评估雌激素和睾酮对动脉和瓣膜发育和功能的影响。它将利用血管细胞的体外培养模型，并开发新的动脉和瓣膜钙化的体内小鼠模型。研究将涉及通过使用生化测定和荧光探针定量钙和磷酸盐沉积来评估体外和体内钙化。这将包括使用最先进的PET/计算机断层扫描（CT）扫描（目前用于评估患者钙化的技术）开发新的体内成像方案。我们还将使用我们的血管钙化模型来研究钙化过程中可能受性激素调节的不同途径的作用;例如Wnt信号传导和自噬。此外，将进行RNAseq和随后的信息学分析，以确定新的基础机制。使用的技术将包括组织学、qPCR、蛋白质印迹、免疫荧光染色和siRNA敲除。培训内容：该项目的监督团队融合了心血管生物学（VEM，PH），钙化生物学（VEM）和化学（PH）以及体内手术和成像（PH）方面的专业知识。培训将主要通过在主管实验室以及负责PET/CT扫描仪的心血管科学中心核心成像设施中实际应用研究技术，分析方法和学习技能。将获得的技能包括细胞和分子生物学技术，显微镜，细胞培养和体内技术。还鼓励学生参加每月的研究研讨会，致力于学生和博士后演讲。预期产出：学生将被鼓励在国际和欧洲科学会议上展示他们的工作，并将有机会与美国夏威夷大学进行科学交流访问。导师的过去的学生通常在学生期间发表至少3篇科学论文，并随后在英国，欧洲和美国获得了备受瞩目的博士后研究职位。参考文献：1. Zhu D，麦肯齐NC，Farquharson C，MacRae VE 2012血管钙化的机制和临床后果。前内分泌。三点九十五分。2. Zhu D，Hadoke PW，Wu J，Vesey AT，Lerman DA，Dweck MR，纽比DE，Smith LB，MacRae VE 2016血管平滑肌细胞雄激素受体的消融证实了睾酮在血管钙化中的作用。Sci Rep 6：24807. 3. www.thenakedscientists.com/articles/interviews/why-do-men-have-more-heart-attacks

Heart disease and strokes affect about one person in three and are in part caused by arteries and valves becoming stiffened with calcium deposits (1). However, how this occurs and why heart disease is more prevalent among men is not fully known. Recent studies by our research group (2,3) have shown that testosterone causes the muscle cells found normally in the walls of arteries to partially transform themselves into bone cells and lay down deposits of calcium salts similar to the substances found in the skeleton. The overall result is a thickening and stiffening of the artery wall and a higher risk for heart disease. This project will assess the influence of oestrogen and testosterone on artery and valve development and function. It will utilise in vitro culture models of vascular cells and develop new in vivo mouse models of arterial and valve calcification. Studies will involve the assessment of calcification in vitro and in vivo through the quantification of calcium and phosphate deposition using biochemical assays and fluorescent probes. This will include the development of novel in vivo imaging protocols using state-of-the-art PET/computedtomography (CT) scanning, a technique currently used to assess calcification in patients. We will also use our models of vascular calcification to investigate the role of different pathways that may be regulated by sex hormones during the calcification process; for example Wnt signalling and autophagy. In addition, RNAseq with subsequent informatics analysis will be undertaken to identify novel underpinning mechanisms. Techniques used will include histology, qPCR, western blotting, immunofluorescent staining and siRNA knockdown. Training: The supervisory team of this project merges expertise in cardiovascular biology (VEM, PH), calcification biology (VEM) and chemistry (PH) and in vivo surgery and imaging (PH). Training will be primarily through practical application of research techniques, analytical methods and study skills in the supervisors' laboratories, as well as The Centre for Cardiovascular Science's core imaging facility, which is responsible for the PET/CT scanner. Skills that will be acquired include cell and molecular biology techniques, microscopy, cell culture and in vivo techniques. Students are also encouraged to attend monthly Research Workshops dedicated to student and post-doctoral presentations. Anticipated outputs: The student will be encouraged to present their work at International and European scientific conferences and will have the opportunity to undertake a scientific exchange visit with The University of Hawaii, USA. Past students of the supervisors' have typically published at least 3 scientific papers during their studentships, and have subsequently secured high profile post-doctoral research positions in the UK, Europe and USA. References: 1. Zhu D, Mackenzie NC, Farquharson C, MacRae VE 2012 Mechanisms and clinical consequences of vascular calcification. Front Endocrinol. 3:95. 2. Zhu D, Hadoke PW, Wu J, Vesey AT, Lerman DA, Dweck MR, Newby DE, Smith LB, MacRae VE 2016 Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification. Sci Rep 6:24807. 3. www.thenakedscientists.com/articles/interviews/why-do-men-have-more-heart-attacks