PCOS and androgen-related disease modeling and drug testing in Multi-organ Integrated Microfluidic Reproductive Platform

项目摘要 已经开发出支持28天生殖周期的微流体系统， 生长、排卵和黄体化以及伴随的雌二醇和孕酮的变化。的 在这种情况下，从卵泡中释放的卵母细胞是健康的，具有预测的核， 体内排卵卵母细胞的细胞质成熟表型。我们整合了卵巢组织， 将激素谱循环到包括人输卵管组织的多路微动力单元中， 子宫内膜、子宫颈和肝类器官。我们还改造了小鼠胰岛， 睾丸和前列腺进入类似的生物活性系统。此应用程序的目的是通过以下方式促进我们的工作 实现下一代微流体系统，该系统是为了实现高性能的目的而创建的。 吞吐量机器人设置，这将使药物测试的综合器官系统，模仿各种 生殖疾病。这个假设将被验证，我们可以创建一个体外微流体系统， 多囊卵巢综合征是一种多器官疾病， 育龄妇女和没有适当体外模型的妇女。在过去4年的工作中， 我们开发了第一代微流控平台， 以上在本申请的目标1中，我们将最终确定一种专门为机器人技术构建的新系统。 实验室该系统是由不吸收类固醇的材料制成的，并且具有 稳定一个月。原型也被机器人处理。车载控制器、泵和 电池已经被改造成低成本、可重复使用的装置， 孵化器以及更大规模的筛选实验室。我们的目标是开发一种设备， 普通的平板培养法可以使生物学家从研究静态废物中的扁平细胞中转移出来， 积累模型。目的二是建立多囊卵巢综合征各器官及相关器官的模型 并测试目标3中的各种药物，这些药物将改变雄激素或胰岛素代谢。这将是 阿斯利康的事总之，我们的研究将提供一个下一代工具箱， 妇女健康和更广泛的细胞生物学领域。

Project Summary Microfluidic systems have been developed that support 28 day reproductive cycles including ovarian follicle growth, ovulation, and luteinization with the accompanying changes in estradiol and progesterone. The oocytes that are released from the follicle in this setting are healthy and have the predicted nuclear and cytoplasmic maturation phenotypes of in vivo ovulated oocytes. We have integrated the ovarian tissue and cycling hormone profiles into a multiplexed microdynamic unit that includes human fallopian tube tissue, uterine endometrium, cervix, and liver organoids. We have also adapted mouse islets and separately, human testis and prostate into similarly bioactive systems. The purpose of this application is to further our work by implementing a next generation microfluidic system that has been created for the express purpose of a high throughput robotics setting that will enable drug testing of integrated organ systems that mimic a variety of reproductive diseases. The hypothesis that will be tested in that we can create an in vitro microfluidic system that represents hallmarks of polycystic ovary syndrome, a multiorgan disease that affects 8-10% of reproductive age women and for whom there is no adequate in vitro model. During the past 4 years of work, we developed the first generation microfluidic platform that permitted the hormone and tissue level function above. In aim 1 of the present application, we will finalize a new system that was built expressly for a robotics laboratory. This system is made of materials that does not absorb steroids and has pumping profiles that are stable up to one month. Prototypes have also been handled robotically. Onboard controllers, pumps and batteries have been adapted with the goal of a low cost, reusable device that could be easily used in an incubator as well as the larger scale-screening laboratory. Our goal is to develop a device that will replace all ordinary plated culture work so that biologists can move away from studying flat cells in static waste- accumulating models. In aim 2 we will establish models of PCOS for each organ and for the organs connected to each other and test a variety of drugs in aim 3 that will alter androgen or insulin metabolism. This will be done with Astrazeneca. Taken together, our studies will provide a next generation toolbox important to women's health and to the broader field of cell biology.