Investigation into the role of ceramide in the pathogenesis of cystic fibrosis lung disease

囊性纤维化是英国最常见的限制生命的遗传性疾病。超过9000人患有CF，大约每2500名新生儿中就有一人受到影响。Cf是一种慢性疾病，与从小就出现并可能在出生时出现的重大医疗问题有关。患有慢性肺囊炎需要每天接受治疗，包括口服药物、雾化器、理疗和特殊饮食，以及频繁的临床就诊和延长住院时间。进行性肺部疾病是慢性肺囊炎最重要的问题，通常会导致年轻人过早死亡。在英国，患有CF的人的平均预期寿命为34岁。虽然我们知道CF是一种遗传性疾病，并涉及细胞内离子通道的问题，但这种肺部疾病的确切原因并不完全清楚。目前的治疗方法无法治愈患者，所有患者都会出现进行性并发症，最明显的是反复出现的肺部感染和炎症，导致肺功能逐渐丧失，最终导致呼吸衰竭。许多患者需要对肺移植进行评估，尽管这并不是一个对每个人都可行的选择，而且供体组织严重短缺。CF研究的一个主要问题是，传统上很难从CF患者的肺内获得高度相关的细胞。我之前的工作是在我的博士期间完成的，由医学研究委员会(MRC)和CF信托培训奖学金资助，通过直接从CF患者在泰恩河畔纽卡斯尔弗里曼医院接受肺移植时取出的病变肺中培养细胞，确定了一种可靠的方法。在这项工作中，我还收集了肺组织作为研究档案。最近，研究人员发现，在一只CF小鼠模型的肺组织中，一种名为神经酰胺的脂肪水平增加。这种蓄积与肺部感染和炎症有关--就像我们在CF患者中看到的那样。在这个目前的项目中，我的目标是使用有价值的人类CF细胞和组织来测量目前存在的神经酰胺水平。然后，我将研究神经酰胺为什么会积聚在CF细胞中，它是如何引起肺部炎症的，重要的是，它可能是一种潜在的新疗法，试图降低神经酰胺水平。我将访问剑桥、巴黎、埃森和纽约的英才中心，并与之合作开展这项工作，并将把在这些中心获得的知识和经验带回纽卡斯尔，以进一步发展纽卡斯尔的研究。

Cystic fibrosis (CF) is the most common life-limiting inherited disease in the United Kingdom (UK). Over 9,000 people have CF and it affects around 1 in 2,500 newborn babies. CF is a chronic condition that is associated with significant medical problems that occur from an early age and may present at birth. Living with CF necessitates a daily burden of treatment, including oral medications, nebulisers, physiotherapy and a special diet, plus frequent clinic visits and prolonged hospital admissions.Progressive lung disease is the most important problem in CF and regularly leads to premature death in young adulthood. The median life expectancy for people with CF in the UK is 34 years. Although we know that CF is a condition that is inherited and involves problems with an ion channel in cells the exact cause of the lung disease is not fully understood. Current treatments do not cure patients, all of whom get progressive complications, most notably recurrent lung infections and inflammation leading to gradual loss of lung function and ultimately respiratory failure. Many patients require assessment for lung transplantation although this is not a viable option for everyone and there is a severe shortage of donor organs.A major problem with CF research is that it has traditionally been difficult to obtain highly relevant cells from inside the lungs of people with CF. My previous work performed during my PhD funded by a Medical Research Council (MRC) and CF Trust Training Fellowship identified a reliable way to do this by growing the cells directly from the diseased lungs removed when people with CF undergo lung transplantation at the Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne. I was also able to collect lung tissue for a research archive during this work.Recently researchers have found increased levels of a fat called 'ceramide' in lung tissue from a CF mouse model. This accumulation was associated with lung infection and inflammation - as we see in people with CF. In this current project I aim to use the valuable human CF cells and tissue to measure the levels of ceramide present. I will then investigate why ceramide may accumulate in CF cells, how it may cause lung inflammation and importantly a potential novel treatment to try and reduce ceramide levels. I will visit and collaborate with centres of excellence in Cambridge, Paris, Essen and New York to perform this work and will bring back knowledge and experience gained in these centres to further develop research in Newcastle.