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

特发性肺纤维化(IPF)是以肺部瘢痕形成(纤维化)为特征的进行性肺部疾病。这种疤痕会使肺部变形，降低肺部吸氧的能力，从而使人感到呼吸困难和咳嗽。目前尚不清楚为什么一些人会患上IPF，但IPF患者往往进展很快而死亡，而且没有治愈方法。在英国，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成为一种值得研究的重要疾病。目前认为，排列在肺内的细胞(上皮细胞)的基因变化使它们容易受到损伤和疤痕形成，尽管这些基因变化如何促进疤痕形成仍不清楚。肺疤痕形成的主要特征是，由于形成疤痕组织的细胞异常高活性，肺部变得小而僵硬。疤痕的形成主要有两种类型的细胞：排列在肺部小气道和气囊中的上皮细胞和产生为肺提供支架的胶水的成纤维细胞。当肺受到损伤时，肺上皮细胞向成纤维细胞发出信号，要求建立更多的支架来帮助修复肺。然而，如果对衬里细胞进行基因重新编程，要求成纤维细胞建立过多的异常支架来应对损伤，它会促进疤痕形成，使肺僵硬并收缩，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是重要的。在IPF中，疤痕从肺的边缘和底部开始，这是拉伸最大的区域。我们的研究表明，当上皮细胞或成纤维细胞拉伸时，与IPF相关的一些基因会影响涉及的通路。此外，当成纤维细胞在僵硬的环境中生长时，例如在有疤痕的肺内，它们会变得更加活跃，并产生更多的疤痕组织。然而，机械力如何影响在IPF中发现的基因变化的细胞，或者基因变化如何影响上皮细胞和成纤维细胞发出的信号仍不清楚。重要的是，基因和细胞信号是否反映了对当前抗纤维化药物反应更好或更差的IPF亚型尚不清楚。这项工作计划将使用一些截然不同但相互补充的科学技术，包括遗传学、细胞和分子生物学，以及临床前建模，以研究上皮衬里细胞和成纤维细胞在肺纤维化发展过程中是如何出错的，以及抗纤维化药物是否可以特异性地针对它们。该计划将重点放在一个关键的分子途径上，即小G蛋白信号通路，它调节这些细胞的机械特性。本项目的目的是了解1)精确定位我们已经观察到的遗传信号，并确定新的遗传信号，以便我们能够在试管实验中准确操纵这些基因2)确定上皮衬里细胞中的遗传信号如何影响RhoA和Rac功能，进而如何改变这些细胞产生的化学信使3)了解铅成纤维细胞中的遗传信号如何导致RhoA和Rac活性改变，以及这对这些细胞的纤维化潜能的影响4)确定这些异常是否会以可被利用来进行个性化治疗的方式在这些细胞中导致不同的影响，以确保正确的患者在正确的时间得到正确的治疗。这项工作将由几个学术研究人员与Galecto Biotech、北欧生物科学公司和Redex Pharma合作进行，以使该计划有最好的机会导致IPF的新疗法。

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.