Integrated Bioengineering Approach to Recovering Antimicrobial Function in Cystic Fibrosis Mucus

CBET-0827293Won本项目调查抗菌素分子和吸入抗生素如何被粘液中的阴离子聚电解质灭活，从而导致持续性呼吸道感染。在囊性纤维化(CF)中，这种感染是一种极端的形式，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，以增强人类的呼吸道防御。本研究将结合最新的同步辐射X射线衍射和计算机模拟，分离和表征感染粘液中内源性抗菌蛋白和阴离子聚电解质成分的静电络合物的结构和稳定性。这是软物质物理学中发展起来的关于水介质中静电相互作用的最新思想的应用。这些结构趋势将在模型系统和囊性纤维化(CF)患者收集的痰中进行检查。利用这一综合知识，将为CF呼吸道的静电环境设计典型的电荷减少的抗菌蛋白质的“不粘”版本。在一种补充方法中，将合理设计和测试用于在呼吸道中溶解抗菌剂和阴离子聚合物之间的静电复合体的生物兼容解结剂。该项目的更广泛影响是：-了解管理这些基本相互作用组合的新规则将对软物质物理和胶体科学产生革命性影响。-未来30年，净水将成为美国和国际上正在出现的危机。通过向受污染的水中添加多价盐，大分子杂质凝聚成聚集体，通过沉淀去除。尽管被广泛使用，但这些过程并没有得到很好的理解。本方案中开发的工程静电相互作用方法将直接与净水冷凝剂的合理设计相关。-在之前的NSF支持中，目前的研究团队成员帮助指导了乌尔巴纳校园女子中学的一个科学奥林匹克团队，并通过让一名高中生参与研究来指导她后来代表美国参加国际科学博览会。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，在适当的情况下，这项工作的成果已被纳入PI的本科生/研究生高级班。

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.