CAREER: Nanomechanics of Bacterial Mucoadhesion and Growth on Healthy and Diseased Human Gut Mucus

该学院早期职业发展（CAREER）奖将支持基础研究，以确定人类肠道中健康和患病粘液分子结构的差异如何改变细菌对粘液的粘附。肠道粘液是微生物防御的第一道防线。生物膜侵入粘液可引起多种人类肠道疾病。这是一个具有挑战性的研究问题，因为粘液分子如何组装，细菌如何粘附在粘液上，以及粘膜生物膜如何在人体肠道中脱落等复杂的相互关联的因素。该研究项目将使用计算建模和模拟来获得对这些因素的纳米级见解。这些见解将有助于加速用于治疗人类肠道疾病的粘膜粘附疗法或抗菌剂的设计。该研究计划还将为本科生，特别是来自代表性不足的群体的多学科研究生教育搭建桥梁，通过基于项目的在线暑期课程，非营利教育组织Station1的课程，以及康奈尔大学航空航天和机械工程（FLAME）计划的未来领导者整合工程，生物和人文科学。该研究计划的具体目标是使用计算建模和模拟：1）确定粘蛋白的超分子组装如何被聚糖组成和结构中的疾病相关变化以及聚糖的细菌酶促降解所改变，2）揭示细菌粘附在粘液表面上的分子机制，为了研究为什么酶促降解和不健康粘蛋白中的聚糖组装体与健康粘蛋白相比具有非常不同的细菌结合特性，和3）阐明粘膜粘附对粘液中细菌生长的影响，以探测生物膜如何粘附于粘液并在粘液降解和生理粘液清除的影响下增殖。该项目的机制见解将有助于加速用于人类肠道药物递送或抗菌剂的粘膜粘附材料的设计，揭示粘液及其聚糖的超分子结构，揭示细菌如何识别和粘附高度异质性聚糖结构域，并确定粘附特性的这些差异最终如何影响粘膜生物膜的脱落动力学。该项目还将为开发工程生物材料提供关键的垫脚石，这些材料专门塑造生物膜的生长，以实现所需的工程目的。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) award will support fundamental research to determine how differences in the molecular structures of healthy and diseased mucus in the human gut can alter the adhesion of bacteria on mucus. Intestinal mucus is the first line of microbial defense. A wide range of human gut disorders can be caused by biofilm invading the mucus. This is a challenging problem to study due to complex interlinked factors of how mucus molecules assemble, how bacteria adhere to mucus, and how mucosal biofilm is shed in the human gut. This research project will use computational modeling and simulations to obtain nanoscale insights on these factors. These insights will help to accelerate the design of mucoadhesive therapeutics or antimicrobials for treating human gut disorders. The research program will also bridge pathways towards multidisciplinary graduate education for undergraduate students, especially from underrepresented groups, by integrating engineering, biological, and humanistic sciences through an online project-based summer course, the curriculum of the nonprofit educational organization, Station1, and the Cornell University’s Future Leaders in Aerospace and Mechanical Engineering (FLAME) program. The specific objectives of this research program are to use computational modeling and simulations to: 1) determine how the supramolecular assembly of mucins is altered by disease-related changes in glycan compositions and structures, and bacterial enzymatic degradation of glycans, 2) uncover the molecular mechanisms of bacterial adhesion on mucus surfaces, to investigate why glycan assemblies in enzymatically degraded and unhealthy mucins will have greatly differing bacterial binding characteristics compared to healthy mucins, and 3) unravel the effects of mucoadhesion on bacterial growth in mucus to probe how biofilms adhere to mucus and proliferate under the influence of mucus degradation and physiological mucus clearance. The mechanistic insights from this project will help to accelerate the design of mucoadhesive materials for drug delivery or antimicrobials for the human gut by revealing the supramolecular structures of mucus and their glycans, unraveling how bacteria recognize and adhere to highly heterogenous glycan domains, and determining how these differences in adhesive characteristics ultimately affect the shedding dynamics of mucosal biofilms. This project will also provide a critical steppingstone towards developing engineered living materials that specifically shapes the growth of biofilms for desired engineering purposes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.