Investigation of MiR-140-5p in Humans and Experimental Models of Pulmonary Arterial Hypertension.

MiR-140-5p 在人类和肺动脉高压实验模型中的研究。

• 批准号: MR/K002406/1
• 负责人: Alexander Rothman
• 金额: $ 26.34万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK002406%2F1
• 关键词: Investigation; MiR; 140; 5p; Humans

Pulmonary Arterial Hypertension:Pulmonary arterial hypertension (PAH) is a devastating and debilitating disease affecting 5 people per million. It is caused by narrowing of the arteries of the lungs and leads to high blood pressure in the lungs and failure of the heart. Severe shortness of breath, heart failure and death are common among sufferers despite recent advances in scientific understanding and clinical treatment of the disease.What Causes Pulmonary Arterial Hypertension?The causes of PAH are incompletely understood. Specific gene mutations are common within families with PAH. This finding had lead to the identification of cellular pathways important in causing PAH. Mutations of BMPR2, a cell surface receptor protein, reduce signalling in the BMPR2 pathway and cause PAH; however, not all patients with mutations of BMPR2 develop the disease. Mutations in other genes leading to reduced BMPR2 signalling can cause PAH and reduced BMPR2 signalling is seen in several experimental models of PAH. These observations have lead to the 'multiple hit' model of pathology in which several genetic 'hits' each reduce BMPR2 signalling and together cause PAH.What are microRNA?MicroRNA are short RNAs that alter the expression of genes within the cell by specifically targeting and preventing the production of proteins. Blood microRNA expression levels have been used as markers of disease in cancer and heart disease. Manipulation of microRNA levels is also used experimentally to treat several diseases. The first human trial of a microRNA based drugs are being undertaken currently.New Findings and Opportunities:The Pulmonary Vascular Research Group in Sheffield has extensive experience in PAH research with expertise in cell culture and experimental models of PAH. The Sheffield Pulmonary Vascular Unit is one of five national centers for clinical investigation of PAH. Prospective collection from patients with newly diagnosed pulmonary hypertension referred to the Sheffield Pulmonary Vascular Unit has created an extensive biobank of blood samples with associated clinical data from over 300 patients.New results from our lab show that patients with PAH have altered microRNA expression patterns in their blood. Further experiments show that reproducing these microRNA changes in human lung artery cells alters the levels of proteins known to regulate BMPR2 signalling. These changes act in a way that would reduce BMPR2 signalling in the manner seen in PAH.Hypotheses:1 Reduced levels of specific microRNA are an important change leading to PAH2 Blood microRNA expression levels may be used as a marker of PAHAims:The aim is to complete our study of microRNA expression in blood samples taken from PAH, examine the effects of altered microRNA expression in human lung cells and test these microRNA as a potential treatment in experimental models of PAH.Experiments:We aim to test our hypothesis by manipulating microRNA levels in human lung artery cells. To determine the effect of the changes in microRNA levels we will asses levels of mRNA and protein of targets within the cell and examine cell growth and movement of cells as indicators of cell function. We will examine expression levels of microRNA expression in experimental models of PAH. Finally we will test a microRNA drug to determine if the changes prevent and treat PAH in experimental models.Conclusion:New findings suggest an exciting link between blood microRNA changes and the mechanisms causing PAH. The Sheffield Pulmonary Vascular Unit blood sample collection provides a unique opportunity to investigate blood microRNAs a biomarker for PAH and the expertise of the Pulmonary Vascular Research Group provide an opportunity to investigate how the observed microRNA changes affect experimental models of PAH.

肺动脉高压：肺动脉高压（PAH）是一种破坏性和使人衰弱的疾病，每百万人中就有5人患病。它是由肺部动脉狭窄引起的，并导致肺部高血压和心脏衰竭。尽管最近对这种疾病的科学认识和临床治疗取得了进展，但严重的呼吸短促、心力衰竭和死亡在患者中很常见。什么原因导致肺动脉高压？多环芳烃的病因尚不完全清楚。特定的基因突变在多环芳烃家族中很常见。这一发现导致了对引起多环芳烃的重要细胞通路的鉴定。细胞表面受体蛋白BMPR2的突变可减少BMPR2通路中的信号传导并导致PAH；然而，并非所有BMPR2突变的患者都会患上这种疾病。导致BMPR2信号传导减少的其他基因突变可引起多环芳烃，在几种多环芳烃的实验模型中可以看到BMPR2信号传导减少。这些观察结果导致了病理学的“多重打击”模型，其中几个遗传“打击”每个减少BMPR2信号并共同导致PAH。什么是microRNA？MicroRNA是一种短rna，它通过特异性靶向和阻止蛋白质的产生来改变细胞内基因的表达。血液中microRNA的表达水平已被用作癌症和心脏病的标志物。操纵microRNA水平也在实验中用于治疗几种疾病。目前正在进行基于microRNA的药物的首次人体试验。新发现和机遇：谢菲尔德的肺血管研究小组在多环芳烃研究方面拥有丰富的经验，擅长细胞培养和多环芳烃实验模型。谢菲尔德肺血管中心是五个国家级多环芳烃临床研究中心之一。来自谢菲尔德肺血管科的新诊断肺动脉高压患者的前瞻性收集已经创建了一个广泛的血液样本生物库，其中包含来自300多名患者的相关临床数据。我们实验室的新结果表明，PAH患者血液中的microRNA表达模式发生了改变。进一步的实验表明，在人肺动脉细胞中复制这些微小rna的变化会改变已知的调节BMPR2信号传导的蛋白质水平。这些变化以一种减少BMPR2信号传导的方式起作用，就像在PAH中看到的那样。假设：1特异性microRNA水平的降低是导致PAH2的重要变化，血液microRNA表达水平可作为PAHAims的标志物：目的是完成我们对PAH血液样本中microRNA表达的研究，检查microRNA表达改变在人肺细胞中的影响，并测试这些microRNA作为PAH实验模型的潜在治疗方法。实验：我们的目标是通过操纵人肺动脉细胞中的microRNA水平来验证我们的假设。为了确定microRNA水平变化的影响，我们将评估细胞内靶细胞的mRNA和蛋白质水平，并检查细胞生长和细胞运动作为细胞功能的指标。我们将检测PAH实验模型中microRNA的表达水平。最后，我们将在实验模型中测试一种microRNA药物，以确定这些变化是否能预防和治疗PAH。结论：新的研究结果表明，血液中microRNA的变化与引起PAH的机制之间存在令人兴奋的联系。谢菲尔德肺血管单位血液样本收集提供了一个独特的机会来研究血液microRNA（多环芳烃的生物标志物），肺血管研究小组的专业知识提供了一个机会来研究观察到的microRNA变化如何影响多环芳烃的实验模型。

项目成果

miRNA-140-5p: new avenue for pulmonary arterial hypertension drug development?

• DOI: 10.2217/epi-2016-0089
• 发表时间: 2016-09
• 期刊: Epigenomics
• 影响因子: 3.8
• 作者: A. Rothman;D. Rowlands;A. Lawrie

A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension.

一种针对骨保护素的治疗性抗体可减轻严重的实验性肺动脉高压。

• DOI: 10.17863/cam.48128
• 发表时间: 2019
• 作者: Arnold N

Response to Letter Regarding Article, "Hemodynamic, Functional, and Clinical Responses to Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension of Different Causes: Phase II Results From the Pulmonary Artery Denervation-1 Study".

对有关文章“不同原因肺动脉高压患者对肺动脉去神经的血流动力学、功能和临床反应：肺动脉去神经-1 研究的 II 期结果”的回复。

• DOI: 10.1161/circinterventions.115.003463
• 发表时间: 2016
• 期刊: Circulation. Cardiovascular interventions
• 作者: Chen SL

Dietary Docosahexaenoic Acid Reduces Oscillatory Wall Shear Stress, Atherosclerosis, and Hypertension, Most Likely Mediated via an IL-1-Mediated Mechanism.

• DOI: 10.1161/jaha.118.008757
• 发表时间: 2018-06-30
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Alfaidi MA;Chamberlain J;Rothman A;Crossman D;Villa-Uriol MC;Hadoke P;Wu J;Schenkel T;Evans PC;Francis SE
• 通讯作者: Francis SE

Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling.

• DOI: 10.1093/cvr/cvt170
• 发表时间: 2013-11-01
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Watson O;Novodvorsky P;Gray C;Rothman AM;Lawrie A;Crossman DC;Haase A;McMahon K;Gering M;Van Eeden FJ;Chico TJ
• 通讯作者: Chico TJ