CAREER: Microbial control of intestinal organoids development and function

职业：肠道类器官发育和功能的微生物控制

• 批准号: 2240045
• 负责人: Abhinav Bhushan
• 金额: $ 55万
• 依托单位: Illinois Institute of Technology
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-15 至 2028-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2240045&HistoricalAwards=false
• 关键词: CAREER; Microbial; control; intestinal; organoids

Each day, Americans take over 200 million oral pills. A major question has been why the same drug does not work for everyone. Gut bacteria could play a significant role in the development of cellular models for drug development and improving their function, but are not currently utilized. Therefore, the goal of this CAREER project is to create microfluidic devices that can incorporate gut bacteria for the controlled generation of intestinal organoids. Through this, the project will also elucidate the role microbes play in modulating functions related to drug absorption. Coupled with these efforts, the research will provide opportunities to underrepresented students in engineering by reaching them early in their curiosity. The educational objectives will leverage the project to create new coursework and a hands-on educational program “Engineering Biology using Microfluidics.” offered as annual workshops on different themes. The program will stimulate excitement in STEM education, in addition to equipping students with 21st-century scientific communication strategies. One long-standing challenge in medicine is the variability in the effectiveness of medicine, which in part is due to the lack of suitable cellular models that capture the variability in drug absorption that comes from diverse gut bacterial species. This is important because the intestine, home to gut bacteria, is the primary site for the absorption of small molecule drugs. Intestinal organoids have enormous potential to mimic organ function in drug development. However, the self-organizing processes underlying organoid development are poorly controlled, which has limited their adoption. A factor that has been largely overlooked is the gut bacteria, which can modulate intestinal function as well as drug absorption and metabolism. Yet, current stem cell derived organoids do not account for gut bacteria. Since gut bacteria are synergistic partners essential to organ development, they could be crucial in steering the controlled generation of organoids. Similarly, current pharmacokinetic models do not account for gut bacteria, which could be the reason for the observed variability in the effectiveness of drugs. These gaps exist because growing the largely anaerobic gut bacterial species with intestinal cells remains a technical challenge in the field. Resolving this challenge could transform the field. The goal of this CAREER project is to engineer a microfluidic device to discover how gut microbes steer the development of intestinal organoids. In parallel, the project will uncover how gut microbes shape the absorptive functions of the small intestine epithelium. The research is built upon previous work in creating a) a microfluidic device with biomimetic freestanding extracellular membrane that enabled the cells to remodel the microenvironment and b) a microfluidic device to simultaneously culture anaerobic bacterial species with intestinal cells. These scientific advances will serve as the foundation for the engineering of small intestine organoids and provide a platform to study microbe-intestinal signaling. The engineered microfluidic devices could also be leveraged to study other organ systems such as the lung, skin, ovary, and tumors where bacterial colonization is increasingly appreciated as a significant functional modulator.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.

每天，美国人服用超过2亿个口服药丸。一个主要的问题是为什么同样的药物不适合所有人。肠道细菌可能在药物开发和改善其功能的细胞模型的发展中起重要作用，但目前尚未使用。因此，该职业项目的目的是创建微流体设备，该设备可以结合肠道细菌的肠道类器官。通过此，该项目还将阐明微生物在调节与药物滥用有关的功能中所扮演的角色。再加上这些努力，该研究将通过好奇地到达工程学的代表性不足的学生。教育目标将利用该项目创建新的课程工作和动手的教育计划“使用微流体学工程生物学”。作为不同主题的年度研讨会。该计划将激发STEM教育的兴奋，除了为学生提供21世纪的科学交流策略。医学中的一个长期挑战是医学有效性的变异性，部分原因是缺乏合适的细胞模型，这些模型捕获了潜水员肠道细菌的药物滥用变异性。这很重要，因为肠道的家园是小分子药物抽象的主要部位。肠癌具有模拟器官在药物发育中的巨大潜力。但是，控制器官发育的基础过程的自组织过程受到控制很差，这限制了其采用。肠道细菌的一个很大程度上被忽视的因素，可以调节肠子功能以及药物滥用和代谢。然而，当前的干细胞衍生的类器官并未解释肠道细菌。由于肠道细菌是器官发育至关重要的协同伴侣，因此它们对于控制受控的器官至关重要。同样，当前的药代动力学模型也不解释肠道细菌，这可能是观察到的药物有效性变异性的原因。之所以存在这些差距，是因为在很大程度上生长具有肠细胞的厌氧肠道细菌仍然是该领域的技术挑战。解决这一挑战可能会改变领域。该职业项目的目的是设计一种微流体设备，以发现肠道微生物如何引导肠道器官的发展。同时，该项目将发现肠道微生物如何塑造小肠上皮的吸收功能。这项研究是基于以前创建A）具有仿生自由式的细胞外膜的微流体设备的工作而建立的，该膜使细胞能够重塑微环境和b）微流体装置，可以轻松培养厌氧菌细菌与肠道细胞。这些科学的进步将成为小肠类器官工程的基础，并为研究微生物 - 肠信号传导提供了平台。工程化的微流体设备也可以被利用来研究其他有机体系统，例如肺，皮肤，卵巢和肿瘤，在该系统中，细菌定植越来越受到赞赏，这是一个重要的功能调节剂。该奖项反映了NSF的法定任务，并认为通过基金会的知识优点和广泛的影响，通过评估来获得评估，认为这是珍贵的。