Molecular Therapies for Cystic Fibrosis Lung Disease

囊性纤维化肺病的分子疗法

基本信息

批准号：
10470331
负责人：
PAUL B MCCRAY
金额：
$ 231.16万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10470331
关键词：
Address Adenine Airway Disease Amphotericin B Animal Model Anions Apical Bacteria Bicarbonates Biology Cells Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Complement Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator DNA Data Deaminase Defect Development Disease Epithelial Cells Family suidae Ferrets Formulation Genetic Diseases Genetic Engineering Goals Guide RNA Host Defense Human In Vitro Infrastructure Ion Channel Knowledge Life Lung Lung diseases Mediating Missense Mutation Modeling Molecular Morbidity - disease rate Mucociliary Clearance Mutation Natural Immunity Nebulizer Nucleotides Pathogenesis Peptides Persons Prevention Property Proteins Pulmonary Cystic Fibrosis RNA Splicing Records Research Research Personnel Respiratory Failure Ribonucleoproteins Role Services Site Surface Techniques Testing Variant Work adeno-associated viral vector airway epithelium airway obstruction airway surface liquid antimicrobial base editing base editor cell type cellular targeting cystic fibrosis airway cystic fibrosis airway epithelia gain of function gene discovery gene repair gene replacement gene therapy in vivo innovation loss of function mortality novel therapeutic intervention novel therapeutics null mutation overexpression prevent progenitor programs protein function recurrent infection repaired small molecule tool

项目摘要

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. !

总体组件项目摘要囊性纤维化（CF）是一种常见的遗传疾病，会导致肺部肺部衰竭复发感染和气道阻塞。尽管我们对CFTR功能的了解已提高自从发现基因以来的30年中，该疾病的治疗仍然是最佳的， CF仍然是渐进的和致命的。小分子CFTR调节剂疗法的进步具有帮助恢复许多突变的蛋白质功能，但大约10％的CF患者没有从这些策略中受益，包括胡说八道和剪接突变的人。中央该提案的主题是开发新的分子疗法，以预防或治疗CF肺部疾病。我们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对肺部疾病发病机理基础的问题，并利用这些知识为新知识提供信息补充CF缺陷的治疗策略，包括基因修复和添加少量形成阴离子通道的分子。三个密切相互关联的项目将共同努力完成以下目标：1）使用目标单核苷酸恢复CFTR功能编辑。我们假设表面气道上皮中的细胞，包括祖细胞的细胞容量可以针对使用基础编辑来修复CFTR突变。 2）了解两性霉素B（ABS）诱导的气道上皮的阴离子分泌的机制，并测试假设AMB可以在体内恢复CF宿主防御能力。 AMB是形成的小分子阴离子通道。 3）确定肺部离子细胞和纤毛细胞中的CFTR表达如何调节气道表面液体的特性，这对于清除和先天性至关重要免疫。必须指导有效的囊性纤维化基因疗法的基因疗法通过清楚地了解疾病的病理生理机制和相关的细胞靶标 CFTR基因置换或编辑。项目负责人及其团队具有协作研究的出色记录，以及在这里，他们将注意力集中在一个共同的目标上。他们的高度创造性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，我们希望加速开发用于CF肺部疾病的新疗法。呢