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: 9265230
• 负责人: Teresa K Woodruff
• 金额: $ 7.24万
• 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/9265230
• 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，发育成熟、健康的配子（卵母细胞），并提供受精的场所和支持胎儿发育的环境。女性生殖道有五个主要器官——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，但整体上支持整体内分泌健康、生育能力和胎儿发育。生殖道器官由多个细胞系组装而成，形成单个卵泡（包围并支持卵母细胞）、输卵管/输卵管、子宫肌层和子宫内膜、子宫颈和阴道。传统上，女性生殖道的研究依赖于分离的原代细胞或在塑料上生长的永生化细胞系的二维（2D）培养，独立于邻近细胞、组织结构和功能背景。转移到三维（3D）培养环境使我们能够更好地了解单个器官内细胞的功能和相互作用，并询问肠道组织之间的相互作用

项目成果

Cadherin-6 type 2, K-cadherin (CDH6) is regulated by mutant p53 in the fallopian tube but is not expressed in the ovarian surface.

• DOI: 10.18632/oncotarget.11499
• 发表时间: 2016-10-25
• 期刊: Oncotarget
• 作者: Karthikeyan S;Lantvit DD;Chae DH;Burdette JE
• 通讯作者: Burdette JE

Endometriosis and ovarian cancer: links, risks, and challenges faced.

• DOI: 10.2147/ijwh.s66824
• 发表时间: 2015
• 期刊: International journal of women's health
• 作者: Pavone ME;Lyttle BM
• 通讯作者: Lyttle BM

Multidrug Resistance Protein 1 Deficiency Promotes Doxorubicin-Induced Ovarian Toxicity in Female Mice.

多药耐药蛋白 1 缺乏会促进多柔比星诱导的雌性小鼠卵巢毒性。

• DOI: 10.1093/toxsci/kfy038
• 发表时间: 2018
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology
• 作者: Wang,Yingzheng;Liu,Mingjun;Zhang,Jiyang;Liu,Yuwen;Kopp,Megan;Zheng,Weiwei;Xiao,Shuo
• 通讯作者: Xiao,Shuo