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Nitric oxide-releasing cystic fibrosis therapeutics

释放一氧化氮的囊性纤维化疗法

基本信息

批准号：
8968231
负责人：
Mark H Schoenfisch
金额：
$ 18.54万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8968231
关键词：
Aerobic Affect Anti-Bacterial Agents Antibiotics Bacteria Biological Assay Burkholderia cepacia Cells Characteristics Chemicals Chemistry Chitosan Clinic Coughing Cystic Fibrosis DNA Sequence Alteration Development Disease Disulfides Engineering Environment Epithelial Cells Future Goals Health Hereditary Disease Human Hydrophobicity Immune Immune system Individual Infection Inherited Kinetics Life Life Expectancy Longevity Lung Measures Mechanics Microbial Biofilms Molecular Weight Morbidity - disease rate Mucins Mucous body substance Nitric Oxide Nitric Oxide Donors Oligosaccharides Pharmaceutical Preparations Polymers Polysaccharides Property Pseudomonas aeruginosa Quality of life Reporting Research Respiratory physiology Role Science Side Solubility Staphylococcus aureus Structure Testing Therapeutic Toxic effect Translating Vertebral column Viscosity Water base cost effective cystic fibrosis patients design fighting gene therapy improved innovation mortality novel pathogen prevent scaffold sound therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Cystic fibrosis is a genetically inherited life-limiting disorder that affects 30,000 people in the US and 70,000 people worldwide. Increased mucus viscosity in the lungs of CF-afflicted individuals prevents the clearance of bacteria via normal means (e.g., ciliary beating and coughing), thereby allowing proliferation and the formation of biofilms. Bacterial biofilms degrade the lungs and are the primary cause of CF morbidity and mortality. While gene therapies could potentially cure CF, there are over 1,800 genetic mutations which cause CF, each of which would require the development of a specific drug. Therefore, development of therapeutics that are more effective than current treatments at eliminating bacterial biofilms represents a more cost effective and timely approach to increasing the life expectancy of people with CF. The goal of this project is to develop water soluble chitosan scaffolds that release nitric oxide (NO), an endogenous antibacterial agent, and effectively eradicate CF biofilms. The efficacy of these novel NO-release scaffolds will be tested against CF-relevant bacteria strains in conditions that mimic the CF lung. We hypothesize that disulfide-reducing reactivity of NO will also reduce the mucus viscosity, potentially enhancing the action of subsequent NO treatments and improving the ability of the innate immune system to further control bacterial levels in the lungs. The effects of NO and NO-release scaffold composition on mucus viscosity will thus be systematically studied to determine NO's potential as a dual action CF therapeutic. These macromolecular scaffolds represent the first NO-based therapeutics suitable for pulmonary delivery, and are thus highly innovative.

描述（由申请人提供）：囊性纤维化是一种遗传性限制生命的疾病，影响美国30，000人和全球70，000人。患有CF的个体的肺中增加的粘液粘度阻止了细菌通过正常手段（例如，纤毛跳动和咳嗽），从而允许增殖和生物膜的形成。细菌生物膜降解肺部，是CF发病率和死亡率的主要原因。虽然基因疗法有可能治愈CF，但有超过1，800种基因突变会导致CF，每一种都需要开发特定的药物。因此，在消除细菌生物膜方面比目前的治疗方法更有效的治疗方法的开发代表了增加CF患者预期寿命的更具成本效益和及时性的方法。本项目的目标是开发水溶性壳聚糖支架，释放一氧化氮（NO），内源性抗菌剂，并有效地消除CF生物膜。这些新型NO释放支架的功效将在模拟CF肺的条件下针对CF相关细菌菌株进行测试。我们假设NO的二硫化物还原反应性也会降低粘液粘度，可能增强后续NO治疗的作用，并提高先天免疫系统进一步控制肺部细菌水平的能力。因此，将系统地研究NO和NO释放支架组合物对粘液粘度的影响，以确定NO作为双重作用CF治疗剂的潜力。这些大分子支架代表了第一个适用于肺部递送的基于NO的治疗剂，因此具有高度创新性。