Integrated Bioengineering Approach to Recovering Antimicrobial Function in Cystic Fibrosis Mucus

CBET-0827293 Wong该项目研究了粘液中的阴离子聚电解质如何灭活抗菌分子和吸入抗生素，从而导致持续性气道感染。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本进展，这项多学科工作旨在设计和测试新的抗菌剂和治疗策略，以增强人体气道防御。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细胞中内源性抗菌蛋白和阴离子抗菌组分的静电复合物的结构和稳定性。粘液这是软物质物理学在水介质中静电相互作用的最新思想的应用。将在模型系统和从囊性纤维化（CF）患者收集的痰中检查这些结构趋势。使用这种组合的知识，原型电荷减少的“不粘”版本的抗菌蛋白将被设计用于CF气道的静电环境。在一种补充方法中，将合理设计和测试旨在溶解气道中抗菌剂和阴离子聚合物之间的静电复合物的生物相容性解粘剂。该项目的更广泛的影响是：-对管理这些基本相互作用组合的新规则的理解将在软物质物理学和胶体科学中产生变革性的影响。- 在未来30年内，水净化将成为美国和国际上的一个新兴危机。通过向受污染的水中加入多价盐，大分子杂质凝结成聚集体，通过沉淀除去。尽管广泛使用，但这些过程并没有得到很好的理解。本建议中开发的工程静电相互作用的方法将直接相关的水净化冷凝剂的合理设计。- 在之前的NSF支持中，本研究团队的成员帮助指导了Urbana女子校园中学的科学奥林匹克团队，并指导了一名高中生，她继续代表美国参加国际科学博览会，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，在适当的情况下，这项工作的结果已被纳入PI的高级本科生/研究生班。

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.