CAREER: Microbial control of intestinal organoids development and function

每天，美国人服用超过2亿片口服药丸。一个主要的问题是为什么同样的药物不适用于所有人。肠道细菌可以在药物开发的细胞模型的开发和改善其功能中发挥重要作用，但目前尚未利用。因此，这个CAREER项目的目标是创建可以结合肠道细菌的微流体设备，以控制肠道类器官的生成。通过这一点，该项目还将阐明微生物在调节与药物吸收相关的功能中所起的作用。再加上这些努力，这项研究将提供机会，以代表性不足的学生在工程，达到他们的好奇心早。教育目标将利用该项目创建新的课程和实践教育计划“使用微流体的工程生物学”。每年举办不同主题的研讨会。该计划将激发STEM教育的兴奋，除了为学生提供21世纪的科学传播策略。 医学中的一个长期挑战是药物有效性的可变性，部分原因是缺乏合适的细胞模型来捕获来自不同肠道细菌物种的药物吸收的可变性。这一点很重要，因为肠道是肠道细菌的家园，是小分子药物吸收的主要场所。肠类器官在药物开发中具有模仿器官功能的巨大潜力。然而，类器官发育背后的自组织过程控制不佳，这限制了它们的采用。一个在很大程度上被忽视的因素是肠道细菌，它可以调节肠道功能以及药物吸收和代谢。然而，目前的干细胞衍生的类器官并不能解释肠道细菌。由于肠道细菌是器官发育必不可少的协同伙伴，因此它们在控制类器官的生成方面可能至关重要。同样，目前的药代动力学模型没有考虑肠道细菌，这可能是观察到的药物有效性变化的原因。这些差距的存在是因为用肠细胞培养主要厌氧的肠道细菌物种仍然是该领域的技术挑战。解决这一挑战可能会改变该领域。这个CAREER项目的目标是设计一个微流体装置，以发现肠道微生物如何引导肠道类器官的发育。同时，该项目将揭示肠道微生物如何塑造小肠上皮的吸收功能。 该研究建立在先前的工作基础上，创造了a）具有仿生独立细胞外膜的微流体装置，使细胞能够重塑微环境，以及B）同时培养厌氧细菌物种和肠细胞的微流体装置。这些科学进展将成为小肠类器官工程的基础，并为研究微生物肠道信号提供平台。工程微流控装置也可用于研究其他器官系统，如肺、皮肤、卵巢和肿瘤，在这些器官系统中，细菌定植作为一种重要的功能调节剂越来越受到重视。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。

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.