Epithelial Regeneration in the Adult Oviduct

项目摘要 尽管女性生殖疾病，如子宫内膜异位症和宫外孕， 令人震惊的是，人们对相关器官的分子或细胞生物学知之甚少。这项建议 重点放在输卵管，因为输卵管作为卵巢和子宫之间的管道，是 哺乳动物受精的部位。虽然输卵管是女性生育的关键部位，但输卵管生理学如何影响女性的生育能力， 在遗传、分子和细胞水平上的调控几乎完全未知。就像所有女性一样 生殖器官，输卵管经历周期性的组织形态发生， 发情周期的激素变化，这是基本的激素调节器，使所有哺乳动物， 包括人类，怀孕。输卵管由单层上皮构成， 多纤毛细胞和分泌细胞。多纤毛细胞（MCCs）从它们的细胞中投射出数百根运动纤毛。 顶面，在那里它们一起跳动，假设捕获排卵的卵母细胞并将其扫过 顺着输卵管MCCs在发情周期中显著重塑：在发情周期的前半段， MCCs的百分比增加并在排卵时达到峰值，之后MCCs的百分比下降 显著虽然输卵管上皮重塑是已知的发生，这是完全不清楚如何这些 重塑事件受到调节。输卵管MCC重构是通过凋亡还是脱附发生的？做茎 细胞参与了这些重塑过程在多纤毛组织中，纤毛会一起跳动，因为组织 平面偏振。在整个发情周期中输卵管平面细胞极性是如何丧失和恢复的？ 最后，这些重塑事件在遗传水平上是如何调节的？这项提案旨在探索输卵管 MCC重塑使用小鼠遗传学、细胞形状的高分辨率成像和 行为，输卵管液流的体内成像和无偏基因组分析。这里提出的工作将 为输卵管多纤毛细胞的更新和输卵管上皮细胞的基因组调控提供了新的见解， 稳态（目的1）和平面细胞极性的建立在输卵管（目的2 周期了解输卵管MCC重塑的遗传、分子和细胞基础 发情周期为治疗女性不孕症和提高体外受精成功率提供了治疗希望 受精

Project Summary Despite the prevalence of female reproductive pathologies, such as endometriosis and ectopic pregnancy, there is shockingly little known about the molecular or cell biology of the organs involved. This proposal focuses on the oviduct, because the oviduct serves as the conduit between the ovary and uterus, and is the site of mammalian fertilization. While the oviduct is a critical site for female fertility, how oviduct physiology is regulated at the genetic, molecular, and cellular level is almost completely unknown. Like all female reproductive organs, the oviduct undergoes recurrent tissue morphogenesis in response to the cyclical hormonal changes of the estrous cycle, which is the fundamental hormonal regulator that allows all mammals, including humans, to become pregnant. The oviduct is lined by a single layer of epithelium which is composed of multiciliated and secretory cells. The multiciliated cells (MCCs) project hundreds of motile cilia from their apical surface, where they beat together and are hypothesized to capture the ovulated oocyte and sweep it down the oviduct. The MCCs remodel dramatically during the estrous cycle: during the first half of the cycle, the percentage of MCCs increases and peaks at ovulation, after which the percentage of MCCs decreases significantly. While oviduct epithelial remodeling is known to occur, it is completely unclear how these remodeling events are regulated. Does oviduct MCC remodeling occur via apoptosis or deciliation? Do stem cells participate in these remodeling events? In multiciliated tissues, cilia beat together because the tissue is planar polarized. How is planar cell polarity of the oviduct lost and regained throughout the estrous cycle? Finally, how are these remodeling events regulated at the genetic level? This proposal seeks to explore oviduct MCC remodeling using a combination of mouse genetics, high resolution imaging of cell shapes and behaviors, in vivo imaging of oviduct fluid flow, and unbiased genomic analysis. The work proposed here will provide new insights into the turnover of oviduct multiciliated cells and the genomic control of oviduct epithelial homeostasis (Aim 1), and the establishment of planar cell polarity in the oviduct (Aim 2) during the estrous cycle. Understanding the genetic, molecular, and cellular basis of MCC remodeling of the oviduct during the estrous cycle holds therapeutic promise for treating female infertility and improving the success rates of in vitro fertilization.