Epithelial Regeneration in the Adult Oviduct

成人输卵管上皮再生

• 批准号: 10542901
• 负责人: Elle Roberson
• 金额: $ 3.59万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542901
• 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; 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; epithelium regeneration; female fertility; fluid flow; high resolution imaging; improved; in vivo; in vivo imaging; insight; loss of function; mouse genetics; 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.

项目摘要 尽管女性生殖疾病的流行，如子宫内膜异位症和异位妊娠， 对相关器官的分子或细胞生物学知之甚少。该提案的重点是 输卵管，因为输卵管作为卵巢和子宫之间的管道，并且是 哺乳动物受精虽然输卵管是女性生育的关键部位，但输卵管生理学如何调节 在基因、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， 输卵管经历周期性的组织形态发生，以响应输卵管的周期性激素变化。 发情周期，这是基本的激素调节，使所有哺乳动物，包括人类， 怀孕了输卵管由单层上皮构成， 分泌细胞多纤毛细胞（MCCs）从其顶端表面投射数百根运动纤毛， 它们一起跳动，并被假设为捕获排卵的卵母细胞并将其沿着输卵管扫下。的 MCCs在发情周期中急剧重塑：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MCC的百分比显著降低。当输卵管 虽然已知会发生上皮重塑，但完全不清楚这些重塑事件是如何调节的。 输卵管MCC重构是通过凋亡还是脱附发生的？干细胞参与了这些重塑吗 事件？在多纤毛组织中，纤毛一起跳动，因为组织是平面极化的。平面细胞怎么样 在整个发情周期中输卵管极性的丧失和恢复？最后，这些重塑事件 在基因水平上进行调控？该建议旨在探索输卵管MCC重塑使用的组合， 小鼠遗传学，细胞形状和行为的高分辨率成像，输卵管液流的体内成像，以及 无偏见的基因组分析本文的工作将为研究输卵管的周转提供新的思路 多纤毛细胞和输卵管上皮稳态的基因组控制（Aim 1），以及建立 平面细胞极性在输卵管（目的2）在发情周期。了解基因、分子和 动情周期期间输卵管MCC重塑的细胞基础为治疗输卵管癌提供了治疗前景。 女性不孕症和提高体外受精的成功率。