CAREER: Microbial control of intestinal organoids development and function

每天，美国人服用超过2亿片口服药片。一个主要的问题是，为什么同一种药物并不是对所有人都有效。肠道细菌可以在药物开发和改善其功能的细胞模型的开发中发挥重要作用，但目前尚未得到利用。因此，这个职业项目的目标是创造能够结合肠道细菌的微流控设备，以控制肠道有机物质的生成。通过这个项目，该项目还将阐明微生物在调节与药物吸收相关的功能方面所起的作用。再加上这些努力，这项研究将通过及早接触到他们的好奇心，为工程学中代表性不足的学生提供机会。教育目标将利用该项目创建新的课程作业和实践教育计划“使用微流控技术的工程生物学”。作为不同主题的年度研讨会提供。除了向学生传授21世纪的科学传播策略外，该项目还将激发STEM教育的兴奋感。医学上的一个长期挑战是药物有效性的变异性，这在一定程度上是因为缺乏合适的细胞模型来捕捉来自不同肠道细菌物种的药物吸收的变异性。这一点很重要，因为肠道是肠道细菌的家园，是吸收小分子药物的主要场所。肠道有机化合物在药物开发中具有模拟器官功能的巨大潜力。然而，有机体发育的自组织过程控制不力，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的吸收和代谢。然而，目前干细胞衍生的有机化合物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，它们可能在指导受控制的类有机物生成方面至关重要。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差异的原因。之所以存在这些差距，是因为用肠道细胞培养以厌氧为主的肠道细菌物种在该领域仍然是一项技术挑战。解决这一挑战可能会改变这一领域。这个职业项目的目标是设计一种微流控设备，以发现肠道微生物如何引导肠道有机物质的发展。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。这项研究建立在以前工作的基础上，a)具有仿生的独立细胞外膜的微流体设备，使细胞能够重塑微环境，以及b)同时培养厌氧细菌和肠道细胞的微流体设备。这些科学进展将作为小肠有机化合物工程的基础，并为研究微生物-肠道信号提供平台。设计的微流控设备还可以用于研究其他器官系统，如肺、皮肤、卵巢和肿瘤，在这些系统中，细菌定植日益被视为重要的功能调节器。这一奖项反映了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。

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.