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

多器官集成微流控生殖平台中的 PCOS 和雄激素相关疾病建模和药物测试

基本信息

批准号：
10017982
负责人：
Ji-Yong Julie Kim
金额：
$ 118.17万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017982
关键词：
3D Print Address Adipose tissue Affect Age Alginates American Androgens Animal Disease Models Animals Automation Biological Biology Biomedical Engineering Cardiovascular Diseases Cells Cellular biology Cervix Uteri Development Devices Diagnosis Disease Disease model Drug Targeting Drug toxicity Encapsulated Endocrine Endocrine System Diseases Endometrial Carcinoma Endometrium Engineering Equipment Estradiol Etiology Financial cost Functional disorder Future Generations Goals Growth Health Hepatic Hormones Human Human Biology Hydrogels Hyperandrogenism In Vitro Incubators Individual Infertility Insulin Islets of Langerhans Laboratories Liquid substance Liver Luteal Phase Luteinization Malignant neoplasm of ovary Mammalian Oviducts Menstrual cycle Metabolic Metabolism Metformin Microfluidics Modeling Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Oocytes Organ Organ Model Organoids Ovarian Ovarian Cycles Ovarian Follicle Ovarian Tissue Ovarian hormone Ovary Ovulation Pancreas Pharmaceutical Preparations Pharmacologic Substance Phenocopy Phenotype Physiology Polycystic Ovary Syndrome Power Sources Prevalence Production Progesterone Prostate Public Health Pump Reproductive system Research Robotics Standardization Steroids Syndrome System Techniques Technology Testing Testis Therapeutic Time Tissue Engineering Tissue Model Tissue imaging Tissues Toxic effect Uterus Validation Woman Women&apos s Health Work body system cost cost effective cost effectiveness culture plates design drug development drug efficacy drug testing experimental study high throughput analysis human tissue in vitro Model in vivo innovative technologies insulin sensitizing drugs interest islet myometrium next generation novel drug class proliferative phase Menstrual cycle prototype reproductive response screening three dimensional cell culture tissue culture tool wasting

项目摘要

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.

项目概要已开发出支持 28 天生殖周期（包括卵泡）的微流体系统生长、排卵和黄体化，伴随着雌二醇和黄体酮的变化。这在这种情况下从卵泡释放的卵母细胞是健康的并且具有预测的核和体内排卵卵母细胞的细胞质成熟表型。我们已经整合了卵巢组织和将激素谱循环到包含人类输卵管组织的多重微动力单元中，子宫内膜、子宫颈和肝脏类器官。我们还分别改造了小鼠胰岛和人类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进一步推进我们的工作实施下一代微流体系统，该系统的创建目的是为了实现高吞吐量机器人设置将使模拟各种集成器官系统的药物测试成为可能生殖系统疾病。将测试我们可以创建体外微流体系统的假设代表多囊卵巢综合症的特征，多囊卵巢综合症是一种多器官疾病，影响 8-10% 的女性育龄妇女，并且没有足够的体外模型。在过去4年的工作中，我们开发了第一代微流体平台，允许激素和组织水平功能多于。在本申请的目标 1 中，我们将最终确定一个专门为机器人技术构建的新系统实验室。该系统由不吸收类固醇的材料制成，并且具有以下泵送特性：稳定长达1个月。原型也已由机器人处理。板载控制器、泵和电池的改造目标是成为一种低成本、可重复使用的设备，可以轻松地用于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来取代所有普通平板培养工作使生物学家可以摆脱研究静态废物中的扁平细胞积累模型。在目标 2 中，我们将为每个器官和相关器官建立 PCOS 模型相互交流并测试目标 3 中会改变雄激素或胰岛素代谢的多种药物。这将是用阿斯利康完成。总而言之，我们的研究将提供一个重要的下一代工具箱女性健康以及更广泛的细胞生物学领域。