Integrated Bioengineering Approach to Recovering Antimicrobial Function in Cystic Fibrosis Mucus

恢复囊性纤维化粘液抗菌功能的综合生物工程方法

• 批准号: 0827293
• 负责人: Gerard Wong
• 金额: $ 24万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0827293&HistoricalAwards=false
• 关键词: Integrated; Bioengineering; Approach; Recovering; Antimicrobial

CBET-0827293WongThis project investigates how antimicrobial molecules and inhaled antibiotics are inactivated by anionic polyelectrolytes in mucus, and thereby contribute to persistent airway infections. In cystic fibrosis (CF), such infections take an extreme form and are the primary cause of death. Using recent fundamental advances in bioengineering and biophysics, this multi-disciplinary work aims to design and test new antimicrobials and therapeutic strategies to enhance human airway defense.Using a combination of state-of-the-art synchrotron x-ray diffraction and computer simulations, this research will isolate and characterize the structure and stability of electrostatic complexes of endogenous antibacterial proteins and anionic polyelectrolyte components in infected mucus. This is an application of recent ideas developed in soft matter physics on electrostatic interactions in aqueous media. These structural tendencies will be examined in model systems and in sputum collected from cystic fibrosis (CF) patients. Using this combined knowledge, prototypical charge-reduced "non-stick" versions of antimicrobial proteins will be designed for the electrostatic environment of the CF airway. In a complementary approach, biocompatible unbinding agents designed to dissolve electrostatic complexes between antimicrobials and anionic polymers in the airway will be rationally designed and tested. Broader impacts of the project are:- An understanding of the new rules governing these combinations of fundamental interactions will have a transformative impact in soft matter physics and colloid science. - Water purification will be an emerging crisis both in the U.S. and internationally in the next 30 years. By adding multivalent salts to contaminated water, macromolecular impurities are condensed into aggregates that are removed through sedimentation. Despite widespread use, these processes are not well understood. The methods developed in this proposal for engineering electrostatic interactions will be directly relevant for rational design of condensing agents for water purification. - In the previous NSF support, members of the present research team has helped coach a Science Olympiad team from Campus Middle School for Girls in Urbana, as well as mentored a high school student who went on to represent the US in the International Science Fair, by involving her in research. These efforts will be continued. - The multi-disciplinary nature of the proposed work will provide ample educational opportunities for the new kind of hybrid scientists necessary in this emerging field. Moreover, when appropriate, results from this work have been incorporated into the PI's advanced undergraduate/graduate classes.

本项目研究抗菌分子和吸入抗生素如何被黏液中的阴离子聚电解质灭活，从而导致持续气道感染。在囊性纤维化（CF）中，这种感染采取极端形式，是死亡的主要原因。利用生物工程和生物物理学的最新基础进展，这项多学科的工作旨在设计和测试新的抗菌剂和治疗策略，以增强人类气道防御。利用最先进的同步加速器x射线衍射和计算机模拟相结合，本研究将分离和表征感染粘液中内源性抗菌蛋白和阴离子多电解质成分的静电复合物的结构和稳定性。这是软物质物理学中关于水介质中静电相互作用的最新思想的应用。这些结构倾向将在模型系统和从囊性纤维化（CF）患者收集的痰中进行检查。利用这些综合知识，将为CF气道的静电环境设计原型电荷减少的“不粘”抗菌蛋白。在一个互补的方法中，生物相容性解结合剂被设计用来溶解抗菌剂和阴离子聚合物在气道中的静电复合物，将被合理地设计和测试。对这些基本相互作用组合的新规则的理解将对软物质物理学和胶体科学产生变革性的影响。-未来30年，水净化将成为美国乃至全球的一个新兴危机。通过向受污染的水中添加多价盐，大分子杂质被浓缩成聚集体，通过沉淀去除。尽管这些过程被广泛使用，但人们对它们还不是很了解。在本方案中开发的工程静电相互作用方法将直接关系到水净化冷凝剂的合理设计。-在之前的NSF支持下，本研究团队的成员帮助指导了厄巴纳分校女校的科学奥林匹克队，并指导了一名代表美国参加国际科学博览会的高中生，让她参与研究。这些努力将继续下去。-拟议工作的多学科性质将为这一新兴领域所需的新型混合科学家提供充足的教育机会。此外，在适当的时候，这项工作的结果已被纳入PI的高级本科/研究生课程。