Ex Vivo Female Reproductive Tract Integration In a 3D Microphysiologic System

3D 微生理系统中的离体女性生殖道整合

• 批准号: 9105454
• 负责人: Teresa K Woodruff
• 金额: $ 155.49万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105454
• 关键词: Adopted; Agonist; Androgens; Animals; Architecture; Biocompatible Materials; Biological Assay; Biological Process; Biology; Blood Circulation; Cell Communication; Cell Culture Techniques; Cell Line; Cell Lineage; Cell surface; Cells; Cervix Uteri; Clinical Trials; Coculture Techniques; Complex; Development; Diffusion; Drug Delivery Systems; Drug Kinetics; Drug toxicity; Endocrine; Endocrine Disruptors; Endometrium; Environment; Estrogens; Evaluation; Exocervix; Exposure to; Feedback; Female; Fertility; Fertilization; Fetal Development; Follicle Stimulating Hormone; Functional disorder; Funding; Germ Cells; Goals; Grant; Health; Hormonal; Hormones; Hospitals; Human; Image; In Situ; In Vitro; Individual; Informed Consent; Institutional Review Boards; Learning; Life; Link; Maintenance; Measures; Modeling; Mus; Oocytes; Operative Surgical Procedures; Organ; Organ Culture Techniques; Organoids; Ovarian; Ovarian Follicle; Ovary; Pathologic; Pathology; Perfusion; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenocopy; Physiological; Physiology; Population; Pregnancy; Production; Reproductive Health; Reproductive Physiology; Research; Sampling; Series; Services; Site; Structure; Surface; System; Teaching Hospitals; Testing; Tissue Preservation; Tissue imaging; Tissues; Toxicology; Uterus; Vaccines; Vagina; Woman; Work; Writing; aged; body system; cell type; drug development; drug distribution; female reproductive system; flexibility; hazard; human embryonic stem cell; human female; human tissue; immortalized cell; improved; in vitro Model; in vivo; in vivo Model; monolayer; myometrium; offspring; oocyte maturation; paracrine; pharmacokinetic model; programs; reproductive; reproductive function; reproductive hormone; reproductive organ; reproductive tract; response; scaffold; three dimensional cell culture; tissue culture; toxicant; two-dimensional

DESCRIPTION (provided by applicant): The female reproductive tract is responsible for producing endocrine hormones, developing mature, healthy gametes (oocytes) and providing the site for fertilization and an environment that supports fetal development. There are five main organs in the female reproductive tract-the ovary, fallopian tubes, uterus, cervix and vagina. Each organ is responsible for unique aspects of reproductive function, but act integrally to support overall endocrine health, fertility, and fetal development. The reproductive tract organs are assembled from multiple cell lineages to create individual follicles (that enclose and support oocytes), oviductal/fallopian tubes, uterine myometrium and endometrium, the cervix and the vagina. Traditionally, research of the female reproductive tract has relied on two-dimensional (2D) cultures of isolated primary cells or immortalized cell lines grown on plastic and independent of adjacent cells, tissue architecture, and functional context. Moving to a three-dimensional (3D) culture environment has allowed us to better understand the function and interaction of cells within individual organs and interrogate interactions between tract tissues in co-cultures (e.g., the follicle and the ovarian surface cells, or the uterine myometrium and endometrium) to measure responses to normal reproductive hormones, pathologic conditions (such as high levels of androgens) or exposure to endocrine disruptors. New biomaterials and 3D culture systems have now presented us with the exciting opportunity to create a complete in vitro reproductive tract whereby each of the cultured organs can be assembled into a linked perfusion culture system. Just as the biological function and responses of 2D monolayer cell cultures differ from those of 3D-cultured organoids, we predict that the biology of the reproductive organs when studied in an integrated series will more closely recapitulate the in vivo environment. In Aims 1 and 2, we propose to develop in vitro cultures of human reproductive tissues that phenocopy in vivo function in terms of hormone production and response to the physiologically relevant reproductive hormones follicle-stimulating hormone (FSH) and estrogen. We will use the 3DKUBE" culture platform (KIYATEC), which not only permits control of perfusion to mimic tissue circulation, automated sampling for pharmacokinetic analyses, tissue imaging and in situ bioassays, but also will facilitate integration of the individal organ cultures into a functional in vitro female reproductive tract culture system in Aim 3. The successful development of an ex vivo female reproductive tract will give us the unique ability to interrogate normal hormonal responses of each organ in the context of the complete reproductive tract, as well as examine responses of the organs and system to agents that pose reproductive hazards. Toxicologic testing on female reproductive function and fertility is currently limited to animal studies. Our proposed Ex Vivo Female Reproductive Tract Integration In a 3D Microphysiologic System would permit earlier assessment of the effects of drugs, toxicants or vaccines on the human female reproductive system prior to exposure in clinical trials.

描述（由申请人提供）：女性生殖道负责产生内分泌激素，发展成熟，健康的配子（卵母细胞），并为受精和支持胎儿发育的环境提供场地。女性生殖道中有五个主要器官 - 卵巢，输卵管，子宫，子宫颈和阴道。每个器官都负责生殖功能的独特方面，但其基础是支持整体内分泌，生育能力和胎儿发育。从多个细胞谱系组装了生殖道器官，以产生单个卵泡（包围和支撑卵母细胞），卵形/输卵管，子宫肌层和子宫内膜，子宫颈和阴道。传统上，对女性生殖道的研究取决于分离的原代细胞的二维（2D）培养物或在塑料上生长的永生细胞系，独立于相邻细胞，组织结构和功能性环境。转移到三维（3D）培养环境使我们能够更好地了解单个器官中细胞的功能和相互作用 共培养（例如，卵泡和卵巢表面细胞，子宫肌层和子宫内膜），以测量对正常生殖激素的反应，病理状况（例如高水平的雄激素）或暴露于内分泌干扰物。现在，新的生物材料和3D培养系统为我们提供了一个令人兴奋的机会，可以创建一个完整的体外生殖道，从而将每个培养的器官都可以组装成一个链接的灌注培养系统。正如2D单层细胞培养物的生物学功能和反应不同于3D培养的器官的生物学功能和反应一样，我们预测，在综合系列中研究时生殖器官的生物学将更加紧密地概括体内环境。在目标1和2中，我们建议开发人类生殖组织的体外培养物，这些组织在体内的表现在激素的产生以及对生理相关的生殖激素促卵泡激素（FSH）和雌激素方面的反应。我们将使用3dkube“培养平台（Kiyatec），它不仅允许控制模仿组织循环，自动取样，进行药代动力学分析，组织成像和原位生物测定，而且还将促进个人培养在VITO SERTACT SYTRACT SYTRACT SYTRACT SYTRACT STRACT SYTRADS STRACT STRACT SYTRAD SYTROD SYTROD 3。让我们在完全生殖道的背景下审问每个器官的正常荷尔蒙反应，并检查对构成生殖危害的器官和系统对女性生殖功能的毒理性测试的反应。在临床试验中暴露之前，在人类女性生殖系统上的药物，毒物或疫苗。