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

这项教师早期职业发展(CALEAR)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的差异如何改变细菌在粘液上的黏附。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。由于粘液分子如何组装、细菌如何附着于粘液以及粘膜生物膜如何在人体肠道脱落等复杂的相互关联的因素，这是一个具有挑战性的研究问题。这项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洞察。这些见解将有助于加快粘附性疗法或抗菌剂的设计，以治疗人类肠道疾病。该研究计划还将通过基于在线项目的暑期课程、非营利性教育组织Station1的课程以及康奈尔大学的航空航天和机械工程未来领导者(FLOW)计划，整合工程、生物和人文科学，为本科生，特别是来自代表不足的群体的本科生，搭建通往多学科研究生教育的桥梁。本研究计划的具体目标是使用计算机建模和模拟来确定粘蛋白的超分子组装是如何因疾病相关的多糖组成和结构的变化以及细菌对多糖的酶降解而改变的，2)揭示细菌在粘液表面黏附的分子机制，研究为什么酶降解和不健康的粘液中的多糖组装具有与健康粘蛋白截然不同的细菌结合特征，以及3)揭示黏附对粘液中细菌生长的影响，以探索在粘液降解和生理性粘液清除的影响下，生物膜如何附着和增殖粘液。该项目的力学见解将有助于加快设计用于药物输送或抗菌剂的粘附性材料，方法是揭示粘液及其多糖的超分子结构，揭示细菌如何识别和黏附高度异质的糖域，并确定这些粘附性特征的差异最终如何影响粘膜生物膜的脱落动力学。该项目还将提供一个关键的踏脚石，以开发专门用于预期工程目的的工程生物膜的生长。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.