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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. !

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