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

肺纤维化是肺泡或气囊逐渐被瘢痕组织取代，这阻止了器官进行有效的气体交换，目前还没有治愈方法。肺纤维化可由于慢性疾病如特发性肺纤维化（IPF）或呼吸道感染期间的严重上皮损伤而发生。英国每年有6000例IPF新发病例，发病率不断增加，确诊后生存期仅为3-5年。从COVID-19和流感中恢复后，纤维化仍然是对健康的最大威胁之一。迫切需要开发可以改变纤维化进展的新疗法。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。上皮基底细胞（BC）是肺的成体干细胞，在损伤后可以自我更新或分化为所有类型的肺上皮。它们通常有效地修复肺部，但最近的研究表明，纤维化可能会损害基底细胞功能。需要进一步的研究来了解这些细胞是否可以被操纵来控制它们的功能。生长因子在协调肺组织的生长和再生中起重要作用。成纤维细胞生长因子7（FGF 7）特异性结合仅在包括BC的上皮细胞上表达的FGF受体2-IIIb（FGFR 2b）以促进生长和分化。已显示FGF 7在肺纤维化中失调，因此对补充FGF 7以促进修复并减少肺中的纤维化以用于疾病改善疗法存在兴趣。在人类和动物模型中肺损伤后FGF 7蛋白的递送已证明其对肺修复的强大影响，但其使用受到阻碍，因为其必须通过静脉内注射递送，这导致从体内快速消除，到肺的分布差和高毒性。合成信使RNA（mRNA）是一种新兴技术，它指导人体自身的细胞产生一种特定的蛋白质，这种蛋白质具有改变生长因子临床应用的潜力。由mRNA编码的生长因子正在测试人类的心脏和皮肤修复，但从未尝试用于肺部，部分原因是交付方面的挑战。我们先前已经开发了保护合成mRNA并促进其在雾化递送后递送到肺细胞中的材料。本项目将结合我们在mRNA递送方面的经验，以及在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指导损伤后肺修复的新策略。为了实现我们的目标，我们旨在解决三个关键问题：1. FGF 7 mRNA对正常和IPF肺中人基底细胞的存活、增殖和迁移有何影响？2. FGF 7 mRNA能促进人肺类器官基底上皮细胞的分化吗？3.在小鼠模型中局部递送FGF 7 mRNA是否减少损伤后的纤维化并改善肺功能？我们的研究成果将有助于将合成mRNA作为肺部蛋白质生产的平台，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.