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9000人患有CF，每2500个新生儿中就有1个患有CF。CF是一种慢性疾病，与早期发生并可能在出生时出现的重大医疗问题有关。CF患者必须每天接受治疗，包括口服药物、雾化器、物理治疗和特殊饮食，以及频繁的诊所就诊和长期住院。进行性肺部疾病是CF中最重要的问题，经常导致青年期过早死亡。在英国，CF患者的平均预期寿命是34岁。虽然我们知道CF是一种遗传性疾病，涉及细胞中的离子通道问题，但这种肺部疾病的确切原因尚不完全清楚。目前的治疗方法并不能治愈患者，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，尽管这并不是对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,它历来是很难获得高度相关的细胞在肺部的CF患者。我之前我的博士期间工作由医学研究理事会(MRC)和CF信托培训奖学金确定一个可靠的方法,直接从细胞病变的肺切除时CF患者进行肺移植研究所的移植,弗里曼医院,纽卡斯尔。在这项工作中，我还能够收集肺组织作为研究档案。最近，研究人员在CF小鼠模型的肺组织中发现了一种名为“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患者身上看到的那样。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细胞中积聚，它是如何引起肺部炎症的，重要的是，一种潜在的新治疗方法来尝试和降低神经酰胺水平。我将访问剑桥、巴黎、埃森和纽约的卓越中心，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，进一步发展研究。

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.