A microphysiological engineered 3D system to the rescue of ovarian follicles

项目摘要 卵巢卵泡是卵巢的功能性多细胞单位，负责女性的生育能力， 卵巢内分泌功能目前，年轻妇女和青春期前女孩被诊断患有癌症， 卵毒性治疗在保持生育能力方面的选择有限， 化疗是最有希望的治疗方法只有原始和早期初级卵泡存活 冷冻保存为了生长和成熟，卵泡必须被分离并成组培养，因为如果它们死亡， 个别培养。分离的早期卵泡作为组培养具有有限的翻译潜力，因为 不同的发育阶段和不同质量的卵泡在队列中，因此强调需要 开发成功培养早期卵泡的方法。卵泡体外培养成功率低 发展归因于复杂的和知之甚少的旁分泌和自分泌信号之间 卵泡中的细胞，相邻的卵泡及其微环境。我们的整体研究目标是：（a） 鉴定体外早期卵泡活化和生长所必需的关键因子，（B）建立 分泌因子、下游受体和转录之间的网络和功能关系 因素，和（c）建立一个标准化的体外培养系统，促进生长和成熟的早期 毛囊个别。这项研究的新奇和意义在于发现了关键的 控制和指导卵巢卵泡发育早期阶段的因素。应用系统 生物学方法来研究复杂的多细胞类器官结构中的动态过程，如卵泡， 有可能转化为人类卵泡，并研究其他组织的发育和相互作用 类器官和胚胎。

Project Summary Ovarian follicles are the functional multicellular units of the ovary responsible for a woman’s fertility and ovarian endocrine function. Currently, young women and prepubertal girls diagnosed with cancer and facing ovo-toxic treatments have limited options to preserve their fertility, with cryopreservation of ovarian tissue prior to chemotherapy being the most promising route. Only primordial and early-stage primary follicles survive cryopreservation. To grow and mature, follicles have to be isolated and cultured in groups, because they die if cultured individually. Culture of isolated early follicles as groups has limited translational potential, because of different developmental stages and varying quality of follicles in the cohort, thus emphasizing the need to develop approaches to successfully culture early follicles individually. The low success rates of in vitro follicle development are attributed to the complex and poorly understood paracrine and autocrine signaling between the cells in a follicle, neighboring follicles and their microenvironment. Our overall research objectives are: (a) to identify key factors essential for activation and growth of early stage follicles in vitro, (b) to establish networks and functional relationships between secreted factors, downstream receptors and transcription factors, and (c) to create a standardized in vitro culture system that promotes growth and maturation of early follicles individually. The novelty and the significance of the proposed research are in the discovery of key factors that control and direct the earliest stages of ovarian follicle development. Application of a systems biology approach to study dynamic processes in complex multicellular organoid structures, such as follicles, has the potential to translate to human follicles and study the development and interplay in other tissue organoids and embryos.