Investigating lung regeneration and repair pathways in Cystic Fibrosis

囊性纤维化（CF）是一种致命的遗传性疾病，英国有1万多人患有此病，全球有7万人患有此病。它是由囊性纤维化基因的两个突变引起的，该基因影响了一个叫做CFTR的通道，该通道控制着身体大多数器官中盐和水进出细胞的流动。这种有缺陷的盐通道会产生粘稠的粘液，导致肺部、肠道和胰腺等多个器官堵塞。肺部疾病是CF患者健康状况不佳的主要原因，它仍然是一种致命的疾病，因此，今天出生的CF患儿预计只能活到47岁。目前治疗晚期CF肺病的唯一方法是挽救生命的肺移植，但这一选择并不适用于许多CF患者，经常CF患者在等待肺移植时死亡。一种名为CFTR调节剂的新型CF药物的开发现在给许多患者带来了希望。这些药物打开有缺陷的CFTR通道，允许盐和水运输，改善肺部粘液堵塞。新的调节剂现已被证明可以改善CF患者的肺功能，但它们并不能逆转已经遭受的肺损伤。因此，CF患者需要专注于修复受损肺部的治疗。气道含有自己的干细胞，称为基底细胞，可以对损伤做出反应并帮助修复受损组织。基底细胞遍布整个气道，从鼻子一直到肺部的小气道。当气道表面受损时，基底细胞移动覆盖该区域，然后转化各种细胞排列气道并促进愈合。当患有CF的人受到感染时，他们的免疫系统反应过度，释放出损害气道的刺激性化学物质，他们的白细胞杀死细菌的效率比没有CF的人低，导致肺部损伤增加。即使用抗生素治疗，我们知道CF患者的气道也不能像非CF患者那样修复。他们的基底细胞转化为更多的粘液分泌细胞和更少的粘液分泌细胞，即纤毛细胞。这意味着更多的粘液聚集在他们的气道中，使他们更容易受到胸部感染，感染和错误修复的恶性循环继续下去。我们现在可以从鼻子中提取基底细胞，并将它们生长在三维凝胶中，形成称为类器官的微小细胞球。这些结构可以显示气道受损时如何修复。它们甚至在内部产生自己的粘液。目的：我们计划使用从CF患者身上取样的基底细胞制成的类器官，并利用这些器官来弄清楚为什么CF肺的修复过程不同。我们也会在接受调剂治疗前后从鼻子中提取细胞，看看这是否会改变基底细胞的行为方式，希望能找到新的方法来帮助CF肺修复。潜在应用：随着时间的推移，我们希望这将使我们能够开发出治疗方法，通过利用肺自身干细胞的力量，使CF肺“从内部自愈”，避免CF患者发展为严重的肺部疾病和肺移植。

Cystic Fibrosis (CF) is a lethal inherited condition affecting over 10,000 people in the UK and 70,000 people worldwide. It is caused by having two mutations in the Cystic Fibrosis gene which affects a channel called CFTR that controls the flow of salt and water in and out of cells in most organs of the body. This faulty salt channel creates thick, sticky mucus and causes blockages in multiple organs such as the lungs, the bowel and the pancreas. Lung disease is the main cause of ill health in CF and it remains a deadly condition, such that a child born today with CF is only expected to live until the age of 47. The only present cure for advanced CF lung disease is a life-saving lung transplant, but this option isn't available to many, and often CF patients die whilst awaiting a lung transplant. The development of a new class of CF drugs called CFTR modulators now offers hope to many patients. These drugs open up the faulty CFTR channel allowing salt and water transport and an improvement in mucus blockage in the lungs. Newer modulators have now been shown to improve lung function in people with CF, but they do not reverse the lung damage that has already been suffered. Therefore, treatments focused on repairing damaged lungs are required for people with CF. The airway contains its own stem cells, called basal cells, that respond to injury and help to repair damaged tissue. Basal cells are present throughout the airway, from the nose all the way to the small airways of the lungs. When the surface of the airway is damaged, basal cells move to cover the area and then transform a variety of cells that line the airway and promote healing. When people with CF get an infection, their immune system responds excessively, releasing harsh chemicals that damage the airways, and their white blood cells are less effective at killing the bacteria than someone without CF, leading to increased damage within their lungs. Even when treated with antibiotics we know that the CF airways don't repair in the same way as people without CF. Their basal cells transform into more mucus secreting cells and fewer cells to move the mucus, known as cilliated cells. This means more mucus collects in their airways, leaving them more prone to chest infections, and a vicious circle of infection and faulty repair continues. We can now take basal cells from the nose and grow these in 3 dimensional gels to form tiny balls of cells called organoids. These structures can show how the airways would repair when damaged. They even create their own mucus on the inside. Aims:We plan to use organoids made from basal cells that we have sampled from people with CF and use these to figure out why the process of repair is different in the CF lung. We will also take cells from the nose before and after treatment with modulator therapy, to see if this changes the way basal cells behave, and hopefully learn new ways by which we can help the CF lung repair. Potential applications:In time, we hope this will allow us to develop treatments that will allow the CF lung to "heal itself from within" by harnessing the power of the lungs own stem cells and avoid the progression of people with CF to severe lung disease and lung transplant.