Gender, age and oestrogen metabolism

性别、年龄与雌激素代谢

• 批准号: 1642381
• 金额: --
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1642381
• 关键词: Gender; age; oestrogen; metabolism

Priority area: Basic Bioscience Underpinning HeathKeywords: LC-MS, pulmonary circulation, oestrogen metabolism Abstract:Gender exerts profound influences on vascular health and 'healthy ageing'. Women are more at risk of developing cardio-pulmonary dysfunction and this may increase post-menopause. Few studies have, however, directly examined the possibility that gender and age may induce changes on the normal pulmonary vascular function and oestrogen metabolism that might pre-dispose women to vascular risk factors. Here we will determine gender differences in the normal function of the pulmonary vasculature, in particular the role & influence of oestrogen, oestrogen metabolism & oestrogen metabolites.Whilst there are several papers and reviews concerning the influence of oestrogen on the vasculature, the influence of oestrogen metabolites on the normal ageing vasculature is very under-researched. Likewise, the influence of gender on normal proliferative signalling pathways is largely under-investigated. Our preliminary data on human pulmonary artery smooth muscle cells (hPASMCs) suggests there are gender differences in signalling pathways & that oestrogen may be the reason for the gender differences. We have recently demonstrated that oestrogen itself can decrease signalling in hPASMCs through the BMPR2 pathway increase MAPK signalling; hence proliferation of female hPASMCs is greater than in male cells. We have shown that microRNA expression in hPASMCs can be influenced by gender and oestrogens. For example, microRNA96 is decreased in hPASMCs from female lung & this causes an increase in serotonin-induced proliferation via the 5-HT1B receptor. It is emerging that oestrogen metabolites may play a more influential role on normal vasculature function than oestrogen itself. One limitation to these investigations is our ability to actually measure oestrogen metabolism and metabolites in vascular tissue. Over the last two year we have developed a novel HPLC/LC-MS 'steroidomic' method for assessing oestrogen metabolism in hPASMCs. We can now apply this technology to understand the role of oestrogen & oestrogen metabolism in the normal function and ageing of pulmonary arteries. Year 1-2. The student would assist the development of LC-MS techniques to analyse oestrogen metabolites in hPASMCs & plasma We have already identified some metabolites that accumulate in PASMCs & that have either pro- or anti-proliferative effects & at first we will examine these (e.g. 16-OHE1/2, 4-OHE1/2, 2-OHE1/2, 2 and 4-MeOHE1/2). Following this, measurements will be made in plasma at days 7, 14, 21 and 28 of the menstrual cycle from normal healthy volunteers. Similar analysis will be made in samples from post-menopausal women and age-matched men. The student will also examine the expression of key microRNAs in these samples, especially those that may interact with oestrogen metabolism or action (e.g. miRNA-22, miRNA-206, miRNA-27b). Year 2-4. hPASMCs will be derived from healthy men & women & these will be grouped according to age. This will be in collaboration with Nick Morrell (Cambridge). The effects of normal ageing and gender on basal and stimulated oestrogen metabolism will be determined. The influence of oestrogen synthesis & metabolising enzymes on this will be determined by applying aromatase inhibitors such as anastrozole and CYP1B1 inhibitors such as TMS and /or by siRNA techniques to silence these enzymes. In addition, the activity and expression of key signalling pathways will be determined (BMPR2, pERK, pAkt, reactive oxygen species etc). The synthesis of oestrogen will be determined by examining aromatase expression & via aromatase activity assay. The student will also repeat key experiments on other pulmonary cell types such as fibroblasts & also vascular smooth muscle cells from human resistance arteries (from gluteal biopsy material). High fidelity training in in vivo skills is also available if the the student wishes this.

优先领域：基础生物科学支撑健康关键词：LC-MS、肺循环、雌激素代谢摘要：性别对血管健康和“健康衰老”产生深远影响。妇女更容易患上心肺功能障碍，这可能会增加绝经后。然而，很少有研究直接研究性别和年龄可能会引起正常肺血管功能和雌激素代谢的变化，可能使女性易患血管危险因素。在这里，我们将确定肺血管正常功能的性别差异，特别是雌激素的作用和影响，雌激素代谢和雌激素代谢物。虽然有几篇论文和评论关于雌激素对血管的影响，雌激素代谢物对正常老化血管的影响是非常不足的研究。同样，性别对正常增殖信号通路的影响在很大程度上也未得到充分研究。我们对人类肺动脉平滑肌细胞（hPASMCs）的初步研究表明，信号通路存在性别差异，雌激素可能是性别差异的原因。我们最近证明，雌激素本身可以通过BMPR 2途径增加MAPK信号传导，从而减少hPASMCs中的信号传导;因此，雌性hPASMCs的增殖大于雄性细胞。我们已经证明，microRNA在hPASMCs中的表达可以受到性别和雌激素的影响。例如，microRNA 96在来自女性肺的hPASMCs中减少，这导致通过5-HT 1B受体增加了降钙素诱导的增殖。雌激素代谢产物对正常血管功能的影响可能比雌激素本身更大。这些研究的一个限制是我们实际测量血管组织中雌激素代谢和代谢物的能力。在过去的两年中，我们已经开发了一种新的HPLC/LC-MS '类固醇'方法来评估雌激素代谢的hPASMCs。我们现在可以应用这项技术来了解雌激素和雌激素代谢在肺动脉正常功能和老化中的作用。一至二年级。学生将协助开发LC-MS技术来分析hPASMCs和血浆中的雌激素代谢物我们已经确定了一些在PASMCs中积累的代谢物，这些代谢物具有促增殖或抗增殖作用，首先我们将检查这些代谢物（例如16-OHE 1/2，4-OHE 1/2，2-OHE 1/2，2和4-MeOHE 1/2）。此后，将在月经周期的第7、14、21和28天对正常健康志愿者的血浆进行测量。将对绝经后女性和年龄匹配男性的样本进行类似分析。学生还将检查这些样本中关键microRNA的表达，特别是那些可能与雌激素代谢或作用相互作用的microRNA（例如miRNA-22，miRNA-206，miRNA-27 b）。2-4年级。hPASMC将来自健康的男性和女性，这些将根据年龄分组。这将与尼克莫雷尔（剑桥）合作。将确定正常年龄和性别对基础和刺激雌激素代谢的影响。雌激素合成和代谢酶对此的影响将通过应用芳香酶抑制剂如阿那曲唑和CYP 1B 1抑制剂如TMS和/或通过siRNA技术沉默这些酶来确定。此外，还将测定关键信号传导途径的活性和表达（BMPR 2、pERK、pAkt、活性氧等）。雌激素的合成将通过检查芳香酶表达&经由芳香酶活性测定来确定。学生还将重复其他肺细胞类型的关键实验，如成纤维细胞和来自人类阻力动脉的血管平滑肌细胞（来自臀部活检材料）。如果学生愿意，也可以提供体内技能的高保真培训。

项目成果

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

雌激素信号传导和门脉性肺动脉高压：肝病肺血管并发症研究 (PVCLD2)。

• DOI: 10.1002/hep.31314
• 发表时间: 2021-03
• 期刊: Hepatology (Baltimore, Md.)
• 作者: Al-Naamani N;Krowka MJ;Forde KA;Krok KL;Feng R;Heresi GA;Dweik RA;Bartolome S;Bull TM;Roberts KE;Austin ED;Hemnes AR;Patel MJ;Oh JK;Lin G;Doyle MF;Denver N;Andrew R;MacLean MR;Fallon MB;Kawut SM;, for the Pulmonary Vascular Complications of Liver Disease Study Group
• 通讯作者: , for the Pulmonary Vascular Complications of Liver Disease Study Group

Data for analysis of catechol estrogen metabolites in human plasma by liquid chromatography tandem mass spectrometry.

通过液相色谱串联质谱法分析人血浆中儿茶酚雌激素代谢物的数据。

• DOI: 10.1016/j.dib.2019.103740
• 发表时间: 2019
• 期刊: Data in brief
• 影响因子: 1.2
• 作者: Denver N