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The role of transforming growth factor beta superfamily members in the pathogenesis of muscle weakness associated with pulmonary arterial hypertension

转化生长因子β超家族成员在肺动脉高压相关肌无力发病机制中的作用

基本信息

批准号：
MR/K023918/1
负责人：
Benjamin Garfield
金额：
$ 28.14万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK023918%2F1
关键词：
role transforming growth factor beta

项目摘要

Pulmonary arterial hypertension (PAH) is a disease that causes raised blood pressure in blood vessels that pick up oxygen from the lungs. It has a life expectancy similar to some advanced, common cancers. There is treatment available but there is no cure. We now know that PAH is associated with weakness in the muscles in the legs, which contributes to the symptoms that patients experience. It is also becoming clear that rehabilitation can improve patients exercise capacity and reverses the changes seen in their muscle cells. These classes can improve quality of life and may prolong people's lives. Researchers believe that certain proteins found in high levels in the blood of patients with other chronic diseases can affect muscle function and growth. One of these proteins is called growth differentiating factor (GDF) 8, high levels of which are associated with muscle weakness in COPD and heart failure (HF). Interestingly there are drugs available which block the actions of GDF-8 on muscle cells which has been shown in animals to result in increased muscle size. A related protein called GDF-15 is found in elevated levels in patients with PAH, and is linked to prognosis. We started investigating the role of GDF-15 in the development of muscle weakness. In patients with COPD as well as healthy volunteers we found that as GDF-15 levels went up, muscle strength went down. We also found that GDF-15 levels in the blood stayed high after heart surgery only in patients who lost more than about 10% of their thigh muscle size. Furthermore we showed that the mechanism through which GDF-15 changes muscle strength and size is the same as that seen in GDF-8. Finally when we added GDF-15 to muscle cells they became smaller. We believe these preliminary results suggest that GDF-15 may be an important protein in causing muscle weakness in PAH and that it may act through the same mechanisms as GDF-8. We aim to test this theory by finding out where GDF-15 is produced and whether it is associated with muscle weakness in animal models of PAH. We want to discover what happens when we add GDF-15 and drugs that may block its actions to muscle cells, and to find out whether GDF-15 levels in the blood and muscles of patients with PAH are involved in the development of muscle weaknessThe research will be carried out by a PhD student under the supervision of a number of experts in the field of muscle weakness and PAH at Imperial College London. We will take the tissue of rats and mice with pulmonary hypertension and examine where GDF-15 is produced. We will take the muscle tissue of these animals and analyze them to see the whether the levels of these proteins in the muscle is related with weakness. Next we will try and define the effects of these proteins on muscle cells and find out how they cause these effects. We will do this first by adding proteins to growing muscle cells in the lab and then blocking their actions using drugs which may stop GDF-15 binding to these cells. Next we will add genes, which cause increased production of GDF-15 to the muscles of mice. Once we establish that this results in muscle weakness we will try to block their actions by adding further genes which cause release of proteins that stop GDF-15 binding to muscle cells. Finally we will investigate the levels of GDF-15 in the blood of patients with PAH to see whether these are related to muscle weakness. We will also take muscle biopsies from the patients who allow us to, in order that we can examine the way in which GDF-15 may cause muscle weakness in men and women with PAH.We expect this work will lead to a greater understanding of the role of GDF-15 in muscle weakness in patients with PAH. IN addition GDF-15 levels may be important in allowing us to define which patients have muscle weakness. We hope in the future to perform a clinical trial of drugs which block the actions of GDF-15.

肺动脉高压（PAH）是一种导致从肺部吸收氧气的血管血压升高的疾病。它的预期寿命与一些晚期常见癌症相似。有治疗方法，但无法治愈。我们现在知道，多环芳烃与腿部肌肉无力有关，这导致了患者所经历的症状。康复治疗可以提高病人的运动能力，逆转肌肉细胞的变化，这一点也越来越清楚。这些课程可以提高生活质量，延长人们的寿命。研究人员认为，患有其他慢性疾病的患者血液中含量较高的某些蛋白质会影响肌肉功能和生长。其中一种蛋白质被称为生长分化因子（GDF） 8，其高水平与慢性阻塞性肺病和心力衰竭（HF）的肌肉无力有关。有趣的是，有一些药物可以阻断GDF-8对肌肉细胞的作用，这在动物身上已经被证明会导致肌肉大小的增加。一种名为GDF-15的相关蛋白在PAH患者中被发现水平升高，并与预后有关。我们开始研究GDF-15在肌肉无力发展中的作用。在慢性阻塞性肺病患者和健康志愿者中，我们发现随着GDF-15水平的上升，肌肉力量下降。我们还发现，心脏手术后血液中的GDF-15水平只有在大腿肌肉萎缩10%以上的患者中才会保持较高水平。此外，我们发现GDF-15改变肌肉力量和大小的机制与GDF-8相同。最后，当我们将GDF-15加入肌肉细胞时，它们变小了。我们认为，这些初步结果表明，GDF-15可能是导致PAH肌肉无力的重要蛋白质，其作用机制可能与GDF-8相同。我们的目标是通过在多环芳烃动物模型中找出GDF-15的产生位置以及它是否与肌肉无力有关来验证这一理论。我们想要发现当我们加入GDF-15和可能阻止其作用于肌肉细胞的药物时会发生什么，并找出PAH患者血液和肌肉中的GDF-15水平是否与肌肉无力的发展有关。研究将由一名博士生在伦敦帝国理工学院肌肉无力和PAH领域的一些专家的监督下进行。我们将在患有肺动脉高压的大鼠和小鼠的组织中检查GDF-15的产生位置。”我们将对这些动物的肌肉组织进行分析，看看肌肉中这些蛋白质的水平是否与虚弱有关。接下来，我们将尝试定义这些蛋白质对肌肉细胞的影响，并找出它们是如何引起这些影响的。我们将首先在实验室中向生长中的肌肉细胞中添加蛋白质，然后使用可能阻止GDF-15与这些细胞结合的药物来阻断它们的作用。接下来，我们将在小鼠肌肉中添加导致GDF-15产生增加的基因。一旦我们确定这会导致肌肉无力，我们将尝试通过添加进一步的基因来阻止它们的作用，这些基因会释放阻止GDF-15与肌肉细胞结合的蛋白质。最后，我们将研究PAH患者血液中GDF-15的水平，看看它们是否与肌肉无力有关。如果允许的话，我们也会对病人进行肌肉活组织检查，这样我们就可以检查GDF-15是如何导致多环芳烃患者肌肉无力的。我们希望这项工作将使我们更好地了解GDF-15在PAH患者肌肉无力中的作用。此外，GDF-15水平可能对我们确定哪些患者有肌肉无力很重要。我们希望在未来进行阻断GDF-15作用的药物的临床试验。