DEFINING THE ROLE OF ZEB1-DEPENDENT EPITHELIAL-MESENCHYMAL CROSSTALK IN LUNG FIBROSIS

特发性肺纤维化（IPF）是一种危及生命的肺部疾病，肺组织变厚、僵硬和疤痕，限制了进入血液的氧气量。由于血液中含氧量较少，IPF患者可能会因日常活动（如散步）而呼吸困难。在英国，IPF每年影响大约6000人，据估计，全世界每10万人中有13至20人患有IPF。大多数患者在诊断后2-4年内死亡。由于批准的IPF治疗方法只能减缓疾病进展，因此存在大量未满足的医疗需求。结缔组织细胞成纤维细胞在IPF的发展中起着重要作用。这些细胞为肺部的气囊（肺泡）提供结构。在疾病的发展过程中，观察到这些成纤维细胞的特征性变化。在IPF患者中，这些修饰过的细胞含有更多的收缩蛋白，就像那些参与肌肉细胞功能的蛋白一样。它们被称为肌成纤维细胞，负责形成疤痕组织。据信，IPF的发生是由于排列在肺泡囊内的细胞（称为肺泡上皮细胞）受到损伤的结果。通常情况下，当我们受伤时，身体会迅速启动一个愈合反应，一旦伤口被修复，这个反应就会被关闭。如果肺部的气囊受损，这需要成纤维细胞和肺泡上皮细胞之间的精确通信。在IPF中，由于异常通信或重复损伤，愈合继续发生，导致僵硬疤痕组织的积聚，影响肺部正常功能的能力。最近，一种名为ZEB1的因子被确定为负责肺上皮细胞和成纤维细胞之间的通信。来自IPF患者的细胞比来自健康对照的细胞含有更多的这种蛋白质。此外，已经筛选到一些调节ZEB1表达的因子，这些因子可能作为IPF的治疗靶点。在这个项目中，我们建议一个多学科的研究项目，汇集疾病模型和大规模蛋白质研究的专业知识，将揭示ZEB1在控制成纤维细胞和肺泡上皮细胞之间的通讯中的作用，以找出IPF中出现的问题。为了实现这一目标，将使用IPF患者来源的细胞建立三维疾病模型，并使用先进的蛋白质组学技术，允许一次识别和定量许多蛋白质。将对IPF患者的肺冲洗或活检（在常规临床诊断期间获得）进行评估，以确定读数（称为“生物标志物”），这些读数可能有助于了解疾病机制，并识别那些可能在肺部“正常”区域存在疾病的患者。这些信息将直接改善临床试验设计，帮助选择由被测试药物目标引起疾病的患者，并最终帮助为受影响的患者提供咨询和选择最佳治疗类型。该项目的成果将为进一步的研究提供信息，增强我们对IPF的理解，长期目标是为患者提供有效的靶向治疗，以减轻这种毁灭性疾病的症状，提高他们的生活质量，并确定IPF患者的生物标志物。

Idiopathic pulmonary fibrosis (IPF) is a life-threatening condition of the lungs where tissue becomes thickened, stiff, and scarred, limiting the amount of oxygen getting into the blood. With less oxygen in the blood, IPF patients can get breathlessness from everyday activities like walking. IPF affects approximately 6,000 people every year in the UK, with an estimated prevalence of 13 to 20 per 100,000 people worldwide. Most patients die within 2-4 years after diagnosis. As approved therapies for IPF only slow disease progression there is significant unmet medical need.An important role in the development of IPF is played by connective tissue cells called fibroblasts. These cells provide structure to the air sacs (alveoli) in the lungs. During development of the disease, characteristic changes to these fibroblasts are observed. In IPF patients, these modified cells contain increased amounts of contractile proteins, like those involved in muscle cell function. They are known as myofibroblasts, and are responsible for laying down scar tissue. It is believed that IPF occurs as a consequence of damage to the cells that line the air sacs in these lungs, called alveolar epithelial cells. Normally, when we suffer an injury, the body quickly starts a healing response that is switched off once the wound has been repaired. This requires the precise communication between fibroblasts and alveolar epithelial cells if the air sacs in the lungs were damaged. In IPF, due to the abnormal communications or repetitive injuries, healing continues to occur resulting in the build-up of stiff scar tissue that affects the ability of the lungs to function properly. Recently a factor called ZEB1 was identified as being responsible for communication between lung epithelial cells and fibroblasts. Cells from IPF patients contain more of this protein than cells from healthy controls. In addition, some factors have been screened that regulate the expression of ZEB1 and these may work as therapeutic targets for IPF. In this project, it is proposed that a multi-disciplinary research program, bringing together expertise from disease models and large-scale study of proteins, will uncover the role of ZEB1 in the control of communications between fibroblasts and alveolar epithelial cells to work out what goes wrong in IPF. To achieve this, 3-dimensional disease models using IPF patient-derived cells will be established, and advanced proteomic techniques that allow identification and quantification of many proteins at once will be used. Lung washings or biopsies from patients with IPF (obtained during their routine clinical diagnosis) will be evaluated to identify readouts (called 'biomarkers') that might give insight both into disease mechanisms and also identify those patients who may have disease that is present in 'normal' regions of their lungs. This information will directly improve clinical trial design by helping to select patients whose disease is caused by the target of the drug being tested, and will eventually help counselling and selection of the best type of treatment for an affected patient. The outputs of this project will inform further research, enhance our understanding of IPF, and the long-term aim is to provide effective targeted therapies for sufferers to reduce symptoms of this devastating disease and improve their quality of life as well as to identify biomarkers for IPF patients.