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

这个学院早期职业发展（Career）奖将支持基础研究，以确定人类肠道中健康和患病粘液的分子结构差异如何改变细菌对粘液的粘附。肠道粘液是微生物的第一道防线。生物膜侵入黏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，因为粘液分子如何聚集，细菌如何附着在粘液上，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。这个研究项目将使用计算模型和模拟来获得这些因素的纳米级见解。这些见解将有助于加速设计用于治疗人类肠道疾病的黏液疗法或抗菌剂。该研究项目还将通过一个基于在线项目的暑期课程、非营利教育组织Station1的课程以及康奈尔大学航空航天与机械工程未来领导者（FLAME）项目，为本科生（特别是来自代表性不足群体的学生）整合工程、生物和人文科学，搭建通往多学科研究生教育的桥梁。该研究计划的具体目标是使用计算建模和模拟来：1)确定粘蛋白的超分子组装是如何被与疾病相关的聚糖组成和结构的变化所改变的，以及细菌对聚糖的酶降解；2)揭示细菌粘附在黏液表面的分子机制，研究为什么酶降解和不健康的粘蛋白中的聚糖组装与健康的粘蛋白相比具有很大不同的细菌结合特性。3)揭示黏液黏附对细菌生长的影响，探讨在黏液降解和生理黏液清除的影响下，生物膜如何粘附黏液并增殖。通过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的聚糖结构域，并确定这些粘附特性的差异最终如何影响粘膜生物膜的脱落动力学，该项目的机制见解将有助于加速用于人类肠道药物输送或抗菌剂的黏附材料的设计。该项目还将为开发工程生物材料提供一个关键的垫脚石，这些材料专门用于为所需的工程目的塑造生物膜的生长。该奖项反映了美国国家科学基金会的法定使命，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.