Defining the Mechanism of Meiotic Initiation Through Autophagy Pathway

通过自噬途径定义减数分裂起始机制

• 批准号: 10556093
• 负责人: Ning Wang
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-22 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556093
• 关键词: Administrative Supplement; Adult; Affect; Aneuploidy; Autophagocytosis; Biology; Birth; Breast; Chromosome Pairing; Chromosome Segregation; Chromosomes; Collection; DNA biosynthesis; Data; Development; Embryo; Endocrine Glands; Ensure; Estrogens; Etiology; Event; Experimental Designs; FMR1; FXR1 gene; Family; Female; Fertility; Fetal Development; Fragile X Syndrome; Gatekeeping; Gender; Gene Activation; Genes; Genetic; Germ Cells; Grant; Health; Hispanic; Hormones; Knock-out; Knowledge; Link; Mediating; Meiosis; Meiotic Prophase I; Mexico; Mitosis; Molecular; Oocytes; Oogenesis; Outcome; Ovarian; Ovarian Follicle; Ovary; Parents; Pathway interactions; Positioning Attribute; Pregnancy; Process; Progesterone; Proliferating; Proteins; Puberty; Quality Control; RNA-Binding Proteins; Recycling; Regulation; Reporting; Research Personnel; Role; Side; Spermatogenesis; Structure; Structure of primordial sex cell; Testing; Testis; Testosterone; Tretinoin; Vertebrates; Woman; Women' s Health; base; bone health; cohesion; conditional knockout; druggable target; experience; experimental study; fetal; granulosa cell; homologous recombination; human disease; improved; inhibition of autophagy; insight; male; member; men; novel; novel therapeutics; oocyte quality; parent grant; post-doctoral training; postnatal; pregnant; primary ovarian insufficiency; protein degradation; reproductive organ; sex; therapeutic target; transcriptome sequencing

PROJECT SUMMARY The ovary is not only a reproductive organ but also an endocrine organ that produces hormones, including estrogen, testosterone, and progesterone—which are vital to women’s reproductive organ, breast development, bone health, and pregnancy. Thus, the ovary is critical to women’s fertility and health. Inside the ovary, ovarian follicles (oocytes enclosed by granulosa cells) are the basic functional unit. However, early depletion of oocytes is a major cause of primary ovarian insufficiency (POI), which affects 5-10% women worldwide. Oogenesis (formation of oocytes) in women starts during fetal development, when primordial germ cells (PGCs) exit mitosis and enter meiotic prophase I (a process termed “meiotic initiation”) to carry out homologous recombination. This is in contrast with spermatogenesis, which does not occur upon puberty in men. At birth, the ovary is filled with meiotically arrested oocytes in follicle structures. Meiotic initiation is essential for oocyte formation, in that genetic disruption of this process results in a near-complete loss of oocytes in adult ovaries. Additionally, during meiotic prophase I, defective homologous recombination results in meiotic chromosome segregation errors and oocytes carrying an incorrect number of chromosomes (aneuploidy), a leading cause of poor pregnancy and fetal outcomes. Thus, proper meiotic initiation ensures both the quantity and the quality of oocytes. However, the molecular mechanism underlying meiotic initiation is poorly understood. We have reported that stimulated by retinoic acid gene 8 (STRA8), a gatekeeper of meiotic initiation in vertebrates, acts as a suppressor of autophagy. As such, loss of STRA8 results in an uncontrolled autophagy activation in germ cells during both spermatogenesis and oogenesis. Based on this information, the parent grant studies autophagic regulation of meiotic initiation in the context of spermatogenesis. Our hypothesis is that STRA8-mediated suppression of autophagy allows accumulation of proteins required for meiotic gene activation and initiation; in the absence of STRA8, these proteins are degraded by autophagy, precluding meiosis. This Administrative Supplement extends our study from spermatogenesis to oogenesis. We will: 1. Investigate the role of autophagy suppression in meiotic initiation in fetal ovaries; 2. Define the molecular links between autophagy and meiotic initiation in fetal ovaries. Aberrant autophagy due to genetic or environmental causes is often linked to human diseases. Meanwhile, autophagy pathway represents an intriguing druggable target. Thus, upon completion, knowledge gained from Administrate Supplement may provide insights into the etiology of POI from the perspective of autophagy dysregulation and offer novel pretherapeutic opportunities to improve women’s health.

项目摘要 卵巢不仅是一个生殖器官，也是一个产生激素的内分泌器官， 雌激素、睾丸激素和睾酮--它们对女性的生殖器官、乳房发育 骨骼健康和怀孕因此，卵巢对女性的生育和健康至关重要。卵巢内，卵巢 卵泡（被颗粒细胞包围的卵母细胞）是基本的功能单位。然而，卵母细胞的早期消耗 是原发性卵巢功能不全（POI）的主要原因，其影响全世界5-10%的妇女。卵子发生 女性卵母细胞的形成始于胎儿发育期间，即原始生殖细胞（PGCs）退出有丝分裂时。 并进入减数分裂前期I（称为“减数分裂起始”的过程）以进行同源重组。这 与男性青春期不发生的精子发生相反。出生时，卵巢充满了 卵泡结构中减数分裂停滞的卵母细胞。减数分裂起始对于卵母细胞的形成至关重要，在遗传学上， 这一过程的中断导致成年卵巢中卵母细胞几乎完全丧失。此外，在减数分裂期间， 前期I，有缺陷的同源重组导致减数分裂染色体分离错误和卵母细胞 携带不正确数量的染色体（非整倍体），这是导致妊娠不良和胎儿畸形的主要原因。 结果。因此，正确的减数分裂起始保证了卵母细胞的数量和质量。但 目前人们对减数分裂起始的分子机制知之甚少。我们已经报道过， 视黄酸基因8（STRA 8）是脊椎动物减数分裂起始的看门人，是自噬的抑制基因。 因此，STRA 8的缺失导致生殖细胞中不受控制的自噬激活， 精子发生和卵子发生。基于这一信息，父母资助研究自噬调节 精子发生过程中的减数分裂起始。我们的假设是，STRA 8介导的抑制 自噬允许积累减数分裂基因激活和启动所需的蛋白质;在缺乏自噬的情况下， STRA 8，这些蛋白质被自噬降解，阻止减数分裂。本行政补充规定 我们的研究从精子发生到卵子发生。我们将：1.研究自噬抑制在 胎儿卵巢减数分裂起始; 2.定义自噬和胚胎细胞减数分裂起始之间的分子联系 卵巢。由于遗传或环境原因导致的异常自噬通常与人类疾病有关。 同时，自噬途径是一个有趣的药物靶点。因此，一旦完成， 从管理补充中获得的信息可以从以下角度了解POI的病因： 自噬失调，并提供新的治疗前的机会，以改善妇女的健康。