Epithelial Regeneration in the Adult Oviduct

项目摘要 尽管女性生殖疾病盛行，如子宫内膜异位症和异位妊娠，但 令人震惊的是，人们对涉及的器官的分子或细胞生物学知之甚少。这项提案的重点是 输卵管，因为输卵管是卵巢和子宫之间的管道，是卵巢和子宫的部位。 哺乳动物受精。虽然输卵管是女性生育的关键部位，但输卵管生理是如何调节的 在遗传、分子和细胞水平上几乎完全未知。像所有女性生殖器官一样， 输卵管经历反复的组织形态发生，以响应周期性的激素变化 发情周期，这是基本的荷尔蒙调节，允许所有哺乳动物，包括人类， 怀孕了。输卵管由一层单层上皮构成，上皮由多纤毛和 分泌细胞。多纤毛细胞(MCC)从其顶端表面投射出数百个活动纤毛，其中 它们一起敲打，假设捕获排卵的卵母细胞并将其扫入输卵管。这个 MCC在发情周期中戏剧性地重塑：在发情周期的前半段，MCC的百分比 排卵时增加，排卵时达到高峰，之后微囊藻细胞百分率显著下降。而输卵管 上皮重塑是已知发生的，但完全不清楚这些重塑事件是如何调控的。 输卵管系膜细胞重塑是通过细胞凋亡还是细胞分裂发生的？干细胞是否参与了这些重建？ 活动？在多纤毛组织中，纤毛跳动在一起，因为组织是平面极化的。平面单元是怎样的 输卵管的极性在整个发情周期中失而复得？最后，这些重塑事件是如何 在基因水平上受到控制？这项建议寻求探索输卵管MCC重塑的联合使用 小鼠遗传学、细胞形状和行为的高分辨率成像、输卵管液体流动的体内成像，以及 公正的基因组分析。本文提出的工作将为输卵管的周转提供新的见解。 多纤毛细胞与输卵管上皮细胞动态平衡的基因组调控(目标1) 发情周期中输卵管内的平面细胞极性(目标2)。了解遗传、分子和 动情周期输卵管微囊重塑的细胞学基础为治疗提供了希望 女性不孕症和提高体外受精成功率。

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.