Epithelial Regeneration in the Adult Oviduct

成人输卵管上皮再生

• 批准号: 9541144
• 负责人: Elle Roberson
• 金额: $ 5.9万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9541144
• 关键词: Adult; Affect; Apical; Apoptosis; Bypass; Cell Death; Cell Shape; Cells; Cellular biology; Centers for Disease Control and Prevention (U.S.); Cilia; Collaborations; Core-Binding Factor; Development; Ectopic Pregnancy; Embryo; Epithelial; Epithelium; Estrogens; Estrous Cycle; Event; Female; Female infertility; Fertility; Fertility Disorders; Fertilization; Fertilization in Vitro; Genes; Genetic; Genetic Transcription; Genomics; Goals; Homeostasis; Hormonal; Hormonal Change; Human; Image; Infertility; Label; Mammalian Oviducts; Mammals; Medicine; Modeling; Molecular; Molecular Biology; Molecular Genetics; Morphogenesis; Mus; Mutant Strains Mice; Natural regeneration; Oocytes; Optical Coherence Tomography; Organ; Ovary; Ovulation; Pathology; Periodicity; Physiology; Population; Pregnancy Rate; Prevalence; Progesterone; Proteins; Pseudostratified Epithelium; Recurrence; Reporter; Role; Secretory Cell; Site; Surface; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Travel; United States; Uterus; Woman; Women' s Health; Work; apical membrane; cell behavior; cilium motility; college; endometriosis; female fertility; fluid flow; high resolution imaging; improved; in vivo; in vivo imaging; insight; loss of function; mouse model; mutant; novel; planar cell polarity; pregnant; reproductive; reproductive organ; response; stem cell population; stem cells; success; transcriptome; transcriptome sequencing

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.

项目概要 尽管子宫内膜异位症和宫外孕等女性生殖疾病普遍存在， 令人震惊的是，人们对所涉及器官的分子或细胞生物学知之甚少。这个提议 重点关注输卵管，因为输卵管是卵巢和子宫之间的管道，是 哺乳动物受精的场所。虽然输卵管是女性生育的关键部位，但输卵管的生理学是如何变化的？ 在遗传、分子和细胞水平上的调节几乎是完全未知的。像所有女性一样 作为生殖器官，输卵管根据周期性变化经历反复的组织形态发生。 发情周期的荷尔蒙变化，这是所有哺乳动物的基本荷尔蒙调节剂， 包括人类，怀孕。输卵管由单层上皮排列，其组成 多纤毛细胞和分泌细胞。多纤毛细胞 (MCC) 从其细胞中投射出数百个活动纤毛 顶端表面，它们在那里一起跳动，并被假设捕获排卵的卵母细胞并清除它 沿着输卵管。 MCC 在发情周期期间发生显着重塑：在周期的前半段， MCC 的百分比增加并在排卵时达到峰值，之后 MCC 的百分比下降 显著地。虽然已知输卵管上皮重塑会发生，但完全不清楚这些重塑是如何发生的 改造事件受到监管。输卵管 MCC 重塑是通过细胞凋亡还是去纤毛发生的？做干 细胞参与这些重塑事件？在多纤毛组织中，纤毛一起跳动，因为该组织是 平面偏振。在整个动情周期中，输卵管的平面细胞极性是如何丢失和恢复的？ 最后，这些重塑事件在基因水平上是如何调控的？该提案旨在探索输卵管 结合小鼠遗传学、细胞形状的高分辨率成像和 行为、输卵管流体流动的体内成像以及公正的基因组分析。这里提出的工作将 为输卵管多纤毛细胞的周转和输卵管上皮的基因组控制提供新的见解 稳态（目标 1），以及发情期间输卵管平面细胞极性的建立（目标 2） 循环。了解 MCC 输卵管重塑的遗传、分子和细胞基础 动情周期为治疗女性不孕症和提高体外试管成功率提供了治疗前景 施肥。