MICA: Investigating mRNA encoded growth factor to promote epithelial repair in pulmonary fibrosis.

肺纤维化是指肺泡逐渐被疤痕组织取代，使器官无法进行有效的气体交换，目前尚无治愈方法。肺纤维化可能是慢性疾病的结果，如特发性肺纤维化(IPF)或呼吸道感染期间严重的上皮损伤。在英国，每年有6000个新的IPF病例，发病率在增加，确诊后仅存活3-5年。在新冠肺炎和流感康复后，纤维化仍然是对健康的最大威胁之一。目前迫切需要开发能够改变纤维化进程的新疗法，这一需求尚未得到满足。反复的肺损伤和无法正确修复在肺纤维化中起着核心作用，这表明修复过程可能是治疗的重要靶点。上皮基底层细胞(BCS)是肺的成体干细胞，损伤后可自我更新或分化为各种类型的肺上皮细胞。它们通常能够有效地修复肺部，然而最近的研究表明，基础细胞功能可能在纤维化中受到损害。要了解这些细胞是否可以被操纵来控制它们的功能，还需要进一步的研究。生长因子在协调肺组织的生长和再生中起着至关重要的作用。成纤维细胞生长因子7(Fgf7)与成纤维细胞生长因子受体2-IIIb(FGFR2b)特异性结合，促进细胞生长和分化。FGF7已被证明在肺纤维化中调节失调，因此人们有兴趣补充FGF7以促进修复和减少肺纤维化，用于疾病修正治疗。在人和动物模型中，肺损伤后Fgf7蛋白的传递已被证明对肺修复具有强大的影响，但由于它必须通过静脉注射给药，导致其在体内迅速消除，在肺内分布不畅，毒性高，因此其使用受到阻碍。合成信使RNA(RNA)是一项新兴的技术，它指示人体自身的细胞产生一种特定的蛋白质，对如何将生长因子应用于临床具有转化潜力。由信使核糖核酸编码的生长因子正在人类的心脏和皮肤修复中进行测试，但从未被尝试用于肺，部分原因是交付方面的困难。我们之前已经开发出材料来保护合成的mRNA，并在雾化输送后促进其进入肺细胞。这项建议将结合我们在mRNA传递方面的经验，结合肺修复和纤维化方面的专业知识，研究mRNA编码的生长因子作为一种指导肺损伤后修复的新策略。为了实现我们的目标，我们旨在解决三个关键问题：1.Fgf7 mRNA对生存的影响是什么，人正常肺和IPF肺的基底层细胞的增殖和迁移？2.Fgf7 mRNA能否促进人肺器官基底层上皮细胞的分化？3.在小鼠损伤模型中，局部传递Fgf7 mRNA是否能减少纤维化并改善肺功能？我们的研究结果将有助于将合成mRNA作为肺内蛋白质生产的平台应用，可广泛应用于不同的蛋白质靶点，并将使这项开创性技术更接近于改善人类健康。

Fibrosis of the lung is the gradual replacement of alveolar of air sacs with scar tissue that prevents the organ from carrying out efficient gas exchange and currently has no cure. Lung fibrosis can occur as a result of chronic disease such as idiopathic pulmonary fibrosis (IPF) or severe epithelial injury during respiratory infection. There are 6000 new cases of IPF each year in the UK, it is increasing in incidence and survival is only 3-5 years after diagnosis. Fibrosis remains one of the largest threats to health after recovery from COVID-19 and influenza. There is an urgent and unmet need to develop new therapies that can alter the progression of fibrosis. Repeated lung injury and an inability to repair properly play a central role in lung fibrosis, suggesting that repair processes could be important targets for therapy. Epithelial basal cells (BCs) are adult stem cells of the lung that can self-renew or differentiate to all types of lung epithelium after injury. They normally function to repair lungs efficiently, however recent studies suggest that basal cell function might be impaired in fibrosis. Further investigation is required to understand whether these cells can be manipulated to control how they function. Growth factors play an essential role in coordinating growth and regeneration of lung tissue. Fibroblast growth factor 7 (FGF7) binds specifically to FGF receptor 2-IIIb (FGFR2b) expressed only on epithelial cells including BCs to promote growth and differentiation. FGF7 has been shown to be dysregulated in lung fibrosis, as a result there is interest in supplementing FGF7 to promote repair and reduce fibrosis in the lung for disease modifying therapy. Delivery of FGF7 protein after lung injury in human and animal models has demonstrated its powerful influence on lung repair but it's use has been hindered because it must be delivered by intravenous injection which results in rapid elimination from the body, poor distribution to the lung and high toxicity. Synthetic messenger RNA (mRNA) is an emerging technology that instructs the body's own cells to produce a specific protein with transformative potential for how growth factors are applied clinically. Growth factors encoded by mRNA are being tested for heart and skin repair in humans but has never been attempted for the lung, partly due to challenges in delivery. We have previously developed materials to protect synthetic mRNA and facilitate its delivery into lung cells following nebulised delivery. This proposal will bring together our experience in mRNA delivery, with expertise in lung repair and fibrosis to investigate mRNA encoded growth factors as a novel strategy to guide lung repair after injury.In order to achieve our goal, we aim to address three key questions: 1. What is the influence of FGF7 mRNA on survival, proliferation and migration of human basal cells from normal and IPF lungs?2. Can FGF7 mRNA promote differentiation of basal epithelial cells in human lung organoids?3. Does local delivery of FGF7 mRNA reduce fibrosis and improve lung function following injury in a murine model?The outcomes of our research will be instrumental for the application of synthetic mRNA as a platform for protein production in the lung that could be broadly applied to different protein targets and will bring this pioneering technology closer to improving human health.