Molecular Therapies for Cystic Fibrosis Lung Disease

总体组件 项目摘要 囊性纤维化（CF）是一种常见的缩短寿命的遗传性疾病，由于其在肺组织中的分布而导致进行性肺衰竭。 复发性感染和气道阻塞虽然我们对CFTR功能的了解有所提高， 在基因发现后的30年里，对这种疾病的治疗仍然不是最理想的， CF仍然是进行性和致命的。小分子CFTR调节剂疗法的进展 有助于恢复许多突变的蛋白质功能，但大约10%的CF患者没有 受益于这些策略，包括无意义和剪接突变的人。中央 该提案的主题是开发新的分子疗法来预防或治疗CF肺病。 我们的三个项目和四个核心的目标是利用我们的体外和动物模型的力量， 解决肺部疾病发病机制的基本问题，并利用这些知识为新的 治疗策略，以弥补CF缺陷，包括基因修复和增加一个小的 形成阴离子通道的分子。这三个密切相关的项目将共同努力， 实现以下目标：1）使用靶向的单核苷酸恢复CFTR功能 编辑.我们假设，在表面气道上皮细胞，包括那些祖细胞， 能力，可以使用碱基编辑靶向修复CFTR突变。2)了解 目的：探讨氨蝶呤B（AmB）诱导气道上皮细胞阴离子分泌的机制，并检测其对气道上皮细胞阴离子分泌的影响。 AmB可以在体内恢复CF宿主防御的假设。AmB是一种小分子， 阴离子通道3)确定CFTR在肺离子细胞和纤毛细胞中的表达方式 调节气道表面液体的性质，这些性质对于清除和先天性 免疫力必须指导囊性纤维化肺病有效基因疗法的开发 通过对疾病的病理生理机制和相关细胞靶点的清楚理解， CFTR基因替换或编辑。 项目负责人和他们的团队在CF合作研究方面有着出色的记录， 在这里，他们把注意力集中在一个共同目标上。他们极具创造性的研究得到了四个 提供创新基础设施和服务的核心。通过这些研究，我们希望加快 CF肺病新疗法的开发。 !

OVERALL COMPONENT PROJECT SUMMARY Cystic fibrosis (CF) is a common life-shortening genetic disease that causes progressive lung failure due to recurrent infections and airway obstruction. While our knowledge of CFTR function has advanced greatly in the 30 years since the discovery of the gene, treatments for the disease remain suboptimal and CF remains progressive and fatal. Advances with small molecule CFTR modulator therapies have helped restore protein function for many mutations, but approximately 10% of people with CF have not benefited from these strategies, including people with nonsense and splicing mutations. The central theme of this proposal is developing new molecular therapies to prevent or treat CF lung disease. The goal of our three projects and four cores is to exploit the power of our in vitro and animal models to address questions fundamental to lung disease pathogenesis and to use this knowledge to inform new therapeutic strategies to complement CF defects, including gene repair and the addition of a small molecule that forms anion channels. The three closely interrelated Projects will work together to accomplish the following goals: 1) To restore CFTR function using targeted single nucleotide editing. We hypothesize that cells in the surface airway epithelium, including those with progenitor capacity, can be targeted to repair CFTR mutations using base editing. 2) To understand the mechanisms of amphotericin B (AmB)-induced anion secretion in airway epithelia and to test the hypothesis that AmB can restore CF host defenses in vivo. AmB is a small molecule that forms anion channels. 3) To determine how CFTR expression in pulmonary ionocytes and ciliated cells regulates properties of the airway surface liquid that are crucial for clearance and innate immunity. The development of effective gene therapies for cystic fibrosis lung disease must be guided by a clear understanding of pathophysiologic mechanisms of disease and the relevant cellular targets for CFTR gene replacement or editing. The Project Leaders and their teams have outstanding track records of collaborative CF research, and here they sharpen their focus to a common goal. Their highly creative research is supported by four cores that provide innovative infrastructure and services. Through these studies we hope to accelerate the development of new therapeutics for CF lung disease. !