MICA: Defining Endotypes of Pulmonary Fibrosis by Understanding the Functional Consequences of Known, and Novel, Genetic Associations with Disease

MICA：通过了解已知和新的与疾病的遗传关联的功能后果来定义肺纤维化的内型

• 批准号: MR/V00235X/1
• 负责人: Gisli Jenkins
• 金额: $ 260.65万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV00235X%2F1
• 关键词: MICA; Defining; Endotypes; Pulmonary; Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung condition characterised by scarring (fibrosis) of the lungs. This scarring deforms the lungs and reduces the ability of the lungs to take in oxygen, which causes a person to feel breathless and cough. It is not clear why some people develop IPF, but people with IPF often progress quickly to death and there is no cure. Each year 6000 people in the UK die of IPF, more than deaths from most cancers, and more than ovarian, cervical and thyroid cancers combined. This makes IPF an important disease to research. It is currently thought that genetic changes in the cells that line the lung (epithelial cells) make them susceptible to injury and scar formation, although, how these genetic changes promote scarring remains unknown. The main feature of lung scarring is that the lungs become small and stiff due to the abnormally high activity of cells that make scar tissue. There are broadly two types of cell responsible for scar formation: epithelial cells that line the small airways and airsacs of the lung and fibroblasts, that produce the glue that provides the scaffolding for the lung. When the lung is injured epithelial lung cells send signals to fibroblasts asking for more scaffolding to be made to help repair the lung. However, if the lining cells are genetically reprogrammed to ask the fibroblasts to build excessive of abnormal scaffolding in response to injury it promotes scarring that make the lungs stiff, and contract, making the lungs small. Mechanical forces that occur when the lung stretches during breathing, or when the lungs become becomes stiff in IPF, are important in the development of fibrosis. In IPF, scarring begins at the edges and bottom of the lungs, areas that are being stretched the most. Our research has shown that a number the genes associated with IPF affects pathways involved when epithelial cells or fibroblasts are stretched. Furthermore, when fibroblasts grow in stiff surroundings, such as that within a scarred lung, they become even more active and produce more scar tissue. However, how mechanical forces affect cells with genetic changes found in IPF, or how the genetic changes affect the signals the that epithelial cells and fibroblasts send remains unknown. Importantly, whether the genes and cellular signals reflect sub-types of IPF that might respond better, or worse, to the current anti-fibrotic drugs is not knownThis programme of work will use a number of distinct but complementary scientific techniques including genetics, cell and molecular biology, and pre-clinical modelling to investigate how the epithelial lining cells and fibroblasts go wrong during the development of lung fibrosis and whether they can be specifically targeted by anti-fibrotic drugs. The programme will focus on a key molecular pathway, the small G protein signalling pathway, which regulates these cells' mechanical properties. The aim of this project is to understand 1) precisely map the genetic signals we have already observed, and identify new genetic signals so we can accurately manipulate these genes in test tube experiments 2) define how the genetic signals in epithelial lining cells effect RhoA and Rac function and in turn how this alters the chemical messengers generated by these cells 3) understand how genetic signals in fibrblasts of lead to altered RhoA and Rac activity and the effect this has on the fibrotic potential of these cells 4) define whether these abnormalities leads to different effects in these cells in a way that can be exploited to personalise therapy to ensure the right patient gets the right treatment at the right time. The work will be undertaken by several academic investigators in partnership with Galecto Biotech, Nordic Bioscience and Redex Pharma to give the programme the best chance of leading to a new treatment for IPF.

特发性肺纤维化（IPF）是一种以肺瘢痕形成（纤维化）为特征的进行性肺部疾病。这种疤痕使肺部变形，降低了肺部吸入氧气的能力，这会导致一个人感到呼吸困难和咳嗽。目前尚不清楚为什么有些人会患上IPF，但IPF患者通常会迅速进展至死亡，并且无法治愈。英国每年有6000人死于IPF，超过大多数癌症的死亡人数，超过卵巢癌、宫颈癌和甲状腺癌的总和。这使得IPF成为研究的重要疾病。目前认为，肺细胞（上皮细胞）的遗传变化使它们容易受到损伤和瘢痕形成的影响，尽管这些遗传变化如何促进瘢痕形成仍然未知。肺瘢痕形成的主要特征是，由于形成瘢痕组织的细胞的异常高活性，肺变得小而僵硬。大体上有两种类型的细胞负责瘢痕形成：排列在肺的小气道和气囊上的上皮细胞和成纤维细胞，它们产生为肺提供支架的胶。当肺损伤时，肺上皮细胞向成纤维细胞发出信号，要求制造更多的支架来帮助修复肺。然而，如果衬里细胞被基因重新编程，要求成纤维细胞建立过度的异常支架来应对损伤，它会促进疤痕形成，使肺僵硬，收缩，使肺变小。当肺在呼吸过程中伸展时，或当肺在IPF中变得僵硬时，发生的机械力在纤维化的发展中很重要。在IPF中，瘢痕开始于肺的边缘和底部，这些区域被拉伸得最多。我们的研究表明，当上皮细胞或成纤维细胞被拉伸时，与IPF相关的一些基因会影响相关的通路。此外，当成纤维细胞在坚硬的环境中生长时，例如在疤痕肺内，它们变得更加活跃并产生更多的疤痕组织。然而，机械力如何影响IPF中发现的具有遗传变化的细胞，或者遗传变化如何影响上皮细胞和成纤维细胞发送的信号仍然未知。重要的是，基因和细胞信号是否反映了IPF的亚型，这些亚型对目前的抗纤维化药物的反应可能更好或更差，目前尚不清楚。和预临床模型研究上皮衬里细胞和成纤维细胞如何在肺纤维化的发展过程中出错，以及它们是否可以抗纤维化药物的特异性靶向。该计划将侧重于一个关键的分子途径，小G蛋白信号通路，它调节这些细胞的机械特性。该项目的目的是了解1）精确绘制我们已经观察到的遗传信号，并确定新的遗传信号，以便我们可以在试管实验中准确地操纵这些基因2）确定上皮衬里细胞中的遗传信号如何影响RhoA和Rac功能，以及这如何改变这些细胞产生的化学信使3）了解成纤维细胞中的遗传信号如何导致RhoA和Rac活性改变，以及这对这些细胞纤维化潜力的影响4）确定这些异常是否会导致这些细胞中的不同效应，从而可以用于个性化治疗，以确保正确的患者获得在正确的时间进行正确的治疗。这项工作将由几名学术研究人员与Galecto Biotech，Nordic Bioscience和Redex Pharma合作进行，以使该计划有最好的机会为IPF提供新的治疗方法。

项目成果

Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study.

• DOI: 10.1016/s2213-2600(22)00251-x
• 发表时间: 2023-01
• 期刊: The Lancet. Respiratory medicine

The Use of Genetic Information to Define Idiopathic Pulmonary Fibrosis in UK Biobank.

• DOI: 10.1016/j.chest.2022.07.027
• 发表时间: 2023-02
• 期刊: CHEST
• 影响因子: 9.6
• 作者: Leavy, Olivia C.;Allen, Richard J.;Kraven, Luke M.;Morgan, Ann D.;Tobin, Martin D.;Quint, Jennifer K.;Jenkins, R. Gisli;Wain, Louise V.
• 通讯作者: Wain, Louise V.

Alternative genetic models in IPF susceptibility genome-wide association studies to improve power and accuracy

IPF 易感性全基因组关联研究中的替代遗传模型可提高功效和准确性

• 发表时间: 2024
• 期刊: EUROPEAN JOURNAL OF HUMAN GENETICS
• 影响因子: 5.2
• 作者: Hernandez-Beeftink Tamara

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.

• DOI: 10.1164/rccm.202205-0845oc
• 发表时间: 2023-06-01
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7

Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis.

• DOI: 10.1136/thoraxjnl-2021-218563
• 发表时间: 2023-06
• 期刊: Thorax
• 影响因子: 10