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.

项目摘要 尽管女性生殖病态患病率（例如子宫内膜异位症和异位妊娠），但 关于所涉及的器官的分子或细胞生物学鲜为人知。这个建议 专注于输卵管，因为卵形作为卵巢和子宫之间的导管，并且是 哺乳动物施肥的部位。虽然输卵管是女性生育能力的关键部位，但卵形生理的生理方式 在遗传，分子和细胞水平上受调节几乎是完全未知的。像所有女性一样 生殖器官，卵形对周期性进行复发组织形态发生 发情循环的激素变化，这是允许所有哺乳动物的基本激素调节剂 包括人类怀孕。卵形由单层上皮衬里，该上皮组成 多细胞和分泌细胞。多毛细胞（MCC）从其投射数百个纤毛的纤毛 顶部表面，他们一起跳动并假设捕获排卵的卵母细胞并扫除它 向下输卵管。 MCC在发情循环中急剧重塑：在周期的上半年， 在排卵时，MCC的百分比增加和峰值，之后MCC的百分比降低 显著地。虽然已知出现卵形上皮重塑，但完全不清楚这些 重塑事件受到调节。 Oviduct MCC重塑是否通过细胞凋亡或分解发生？做 细胞参加这些重塑事件？在多细胞组织中，纤毛一起跳动，因为组织是 平面极化。在整个发情周期中，输卵管的平面细胞极性如何丧失和恢复？ 最后，如何在遗传水平调节这些重塑事件？该建议旨在探索卵子 使用小鼠遗传学的组合，细胞形状的高分辨率成像和MCC重塑 行为，卵形流体流量的体内成像和无偏基因组分析。这里提出的工作将 提供有关输卵管多细胞的营业额的新见解和卵形上皮的基因组控制 体内平衡（AIM 1），以及在发情期间产卵中的平面细胞极性（AIM 2） 循环。了解在遗传，分子和细胞基础上的MCC重塑过程中的遗传学， 发情循环具有治疗女性不育症和提高体外成功率的治疗诺言 受精。