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

定义 ZEB1 依赖性上皮间质串扰在肺纤维化中的作用

• 批准号: MR/S025480/1
• 负责人: Yihua Wang
• 金额: $ 57.24万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS025480%2F1
• 关键词: DEFINING; ROLE; ZEB1; DEPENDENT; EPITHELIAL

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.

特发性肺纤维化（IPF）是一种危及生命的肺部疾病，其中组织变得增厚，僵硬和疤痕，限制了进入血液的氧气量。由于血液中的氧气较少，IPF患者可以从日常活动（如步行）中获得呼吸困难。在英国，IPF每年影响约6，000人，全球估计患病率为每100，000人中13至20人。大多数患者在诊断后2-4年内死亡。由于已批准的IPF治疗只能减缓疾病进展，因此存在显著的未满足的医疗需求。在IPF的发展中，结缔组织细胞（称为成纤维细胞）发挥着重要作用。这些细胞为肺中的气囊（肺泡）提供结构。在疾病发展过程中，观察到这些成纤维细胞的特征性变化。在IPF患者中，这些修饰的细胞含有增加量的收缩蛋白，如参与肌肉细胞功能的蛋白。他们被称为肌成纤维细胞，并负责铺设疤痕组织。据信，IPF的发生是由于这些肺中排列气囊的细胞（称为肺泡上皮细胞）受损的结果。通常情况下，当我们受伤时，身体会迅速启动愈合反应，一旦伤口修复，这种反应就会关闭。这就需要在肺中的气囊受损时，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性损伤，愈合继续发生，导致僵硬疤痕组织的积聚，影响肺正常功能的能力。最近，一种名为ZEB 1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，已经筛选出一些调节ZEB 1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，建议一个多学科的研究计划，汇集疾病模型和大规模蛋白质研究的专业知识，将揭示ZEB 1在控制成纤维细胞和肺泡上皮细胞之间的通信中的作用，以找出IPF中出现的问题。为了实现这一目标，将建立使用IPF患者来源的细胞的三维疾病模型，并将使用先进的蛋白质组学技术，可以同时鉴定和定量许多蛋白质。将对IPF患者的肺冲洗液或活检（在常规临床诊断期间获得）进行评价，以确定读数（称为“生物标志物”），这些读数可能有助于深入了解疾病机制，并识别可能在肺部“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，帮助选择由受试药物靶点引起疾病的患者，并最终帮助为受影响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，以减少这种毁灭性疾病的症状，改善他们的生活质量，并确定IPF患者的生物标志物。

项目成果

Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis.

• DOI: 10.7554/elife.69348
• 发表时间: 2022-02-21
• 期刊: eLife
• 影响因子: 7.7
• 作者: Brereton CJ;Yao L;Davies ER;Zhou Y;Vukmirovic M;Bell JA;Wang S;Ridley RA;Dean LSN;Andriotis OG;Conforti F;Brewitz L;Mohammed S;Wallis T;Tavassoli A;Ewing RM;Alzetani A;Marshall BG;Fletcher SV;Thurner PJ;Fabre A;Kaminski N;Richeldi L;Bhaskar A;Schofield CJ;Loxham M;Davies DE;Wang Y;Jones MG
• 通讯作者: Jones MG

WDHD1 is essential for the survival of PTEN-inactive triple-negative breast cancer.

WDHD1 对于 PTEN 失活三阴性乳腺癌的生存至关重要

• DOI: 10.1038/s41419-020-03210-5
• 发表时间: 2020-11-21
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Ertay A;Liu H;Liu D;Peng P;Hill C;Xiong H;Hancock D;Yuan X;Przewloka MR;Coldwell M;Howell M;Skipp P;Ewing RM;Downward J;Wang Y
• 通讯作者: Wang Y

Spatially resolved deconvolution of the fibrotic niche in lung fibrosis.

• DOI: 10.1016/j.celrep.2022.111230
• 发表时间: 2022-08-16
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Eyres, Michael;Bell, Joseph A.;Davies, Elizabeth R.;Fabre, Aurelie;Alzetani, Aiman;Jogai, Sanjay;Marshall, Ben G.;Johnston, David A.;Xu, Zijian;Fletcher, Sophie, V;Wang, Yihua;Marshall, Gayle;Davies, Donna E.;Offer, Emil;Jones, Mark G.
• 通讯作者: Jones, Mark G.

Synthetic lethal approaches to target cancers with loss of PTEN function.

• DOI: 10.1016/j.gendis.2022.12.015
• 发表时间: 2023-11
• 期刊: Genes & diseases
• 影响因子: 6.8
• 作者: Ertay A;Ewing RM;Wang Y
• 通讯作者: Wang Y

Respiratory Outcomes in Patients Following COVID-19-Related Hospitalization: A Meta-Analysis.

• DOI: 10.3389/fmolb.2021.750558
• 发表时间: 2021
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Guo T;Jiang F;Liu Y;Zhao Y;Li Y;Wang Y
• 通讯作者: Wang Y