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

MICA：研究 mRNA 编码的生长因子促进肺纤维化中的上皮修复。

• 批准号: MR/W028433/1
• 负责人: Asha Patel
• 金额: $ 69.86万
• 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: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW028433%2F1
• 关键词: MICA; Investigating; mRNA; encoded; growth

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.

肺纤维化是指肺泡或气囊逐渐被疤痕组织取代，从而阻止器官进行有效的气体交换，目前尚无治愈方法。慢性疾病如特发性肺纤维化（IPF）或呼吸道感染期间严重上皮损伤可导致肺纤维化。在英国，每年有6000例新的IPF病例，其发病率正在增加，诊断后的生存期仅为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。目前迫切需要开发新的治疗方法来改变纤维化的进展。反复肺损伤和不能正常修复在肺纤维化中起核心作用，这表明修复过程可能是治疗的重要目标。上皮基底细胞（Epithelial basal cells, BCs）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。它们通常具有有效修复肺的功能，但最近的研究表明，基底细胞功能可能在纤维化中受损。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）特异性结合仅在包括bc在内的上皮细胞上表达的FGF受体2-IIIb (FGFR2b)，促进生长和分化。FGF7已被证明在肺纤维化中失调，因此有兴趣补充FGF7以促进修复和减少肺纤维化，用于疾病修饰治疗。在人体和动物模型中，肺损伤后递送FGF7蛋白已证明其对肺修复的强大影响，但由于必须通过静脉注射递送，导致其从体内迅速消除，分布到肺部的能力差，毒性高，因此其使用受到阻碍。合成信使RNA （mRNA）是一项新兴技术，它指导人体自身细胞产生具有转化潜力的特定蛋白质，用于生长因子的临床应用。由mRNA编码的生长因子正被用于人类心脏和皮肤修复的测试，但从未尝试过用于肺部，部分原因是递送方面的挑战。我们之前已经开发出保护合成mRNA的材料，并促进其在雾化递送后进入肺细胞。该提案将结合我们在mRNA传递方面的经验，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，我们的目标是解决三个关键问题：1。FGF7 mRNA对正常肺和IPF肺基底细胞的存活、增殖和迁移有何影响？fgf7mrna是否能促进人肺类器官基底上皮细胞的分化？在小鼠模型中，局部递送FGF7 mRNA是否能减少损伤后的纤维化并改善肺功能？我们的研究结果将有助于合成mRNA作为肺部蛋白质生产平台的应用，可以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。