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

囊性纤维化（CF）是英国最常见的限制生命的遗传性疾病。超过9，000人患有CF，它会影响大约1/2，500的新生儿。CF是一种慢性疾病，与早期发生的重大医疗问题有关，并可能在出生时出现。患有CF的患者需要每天接受治疗，包括口服药物、雾化器、物理治疗和特殊饮食，以及频繁的门诊和长期住院。进行性肺部疾病是CF最重要的问题，经常导致年轻人过早死亡。在英国，CF患者的平均预期寿命为34岁。虽然我们知道CF是一种遗传性疾病，并且涉及细胞中离子通道的问题，但肺部疾病的确切原因尚未完全了解。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，最明显的是复发性肺部感染和炎症，导致肺功能逐渐丧失，最终呼吸衰竭。许多患者需要评估肺移植，尽管这不是每个人都可行的选择，而且供体器官严重短缺。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。我以前的工作在我的博士学位由医学研究理事会（MRC）和CF信托培训奖学金资助确定了一种可靠的方法来做到这一点，当CF患者在泰恩河畔纽卡斯尔弗里曼医院移植研究所接受肺移植时，直接从病变肺中培养细胞。在这项工作中，我还能够收集肺组织用于研究档案。最近，研究人员在CF小鼠模型的肺组织中发现了一种叫做“神经酰胺”的脂肪水平增加。这种积累与肺部感染和炎症有关-正如我们在CF患者中看到的那样。在目前的项目中，我的目标是使用有价值的人类CF细胞和组织来测量神经酰胺的水平。然后，我将研究为什么神经酰胺可能在CF细胞中积累，它如何导致肺部炎症，重要的是，这是一种潜在的新治疗方法，可以尝试降低神经酰胺水平。我将访问并与剑桥、巴黎、埃森和纽约的卓越中心合作，以执行这项工作，并将带回在这些中心获得的知识和经验，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.