Somatic regulation of embryonic germline dynamics by isoprenoids

类异戊二烯对胚胎种系动力学的体细胞调节

• 批准号: 10660038
• 负责人: Lacy J Barton
• 金额: $ 24.87万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660038
• 关键词: Adolescent; Adult; Animals; Binding; Biogenesis; Biological Assay; Cell membrane; Cell physiology; Coupled; Data; Development; Disease; Drosophila genus; Drosophila melanogaster; Embryo; Embryonic Development; Ensure; Environment; Enzymes; Event; Exhibits; Fertility; Foundations; G-Protein-Coupled Receptors; Gametogenesis; Genes; Genetic Suppression; Genetic Transcription; Germ; Germ Cells; Gonadal structure; Health; House mice; Human; Image; In Vitro; Insecta; Insecticides; Institution; Invertebrates; Isoprene; Juvenile Hormones; Lipids; Mammalian Cell; Mammals; Mass Spectrum Analysis; Measures; Mediating; Meiosis; Mentors; Mission; Modeling; Mus; National Institute of Child Health and Human Development; Nature; Oogenesis; Pattern; Persons; Pharmaceutical Preparations; Phospholipase C; Positioning Attribute; Process; Proteins; Proteomics; Receptor Activation; Regulation; Research; Research Personnel; Role; Sex Differences; Signal Transduction; Source; Spectrometry; Spermatogenesis; Structure of primordial sex cell; Testing; Time; Training; Tretinoin; Work; animal imaging; base; cell motility; experimental study; hormonal signals; hormone analog; in vitro Assay; in vivo; insight; isoprenoid; male; metabolomics; microscopic imaging; next generation; non-genomic; novel; prevent; programs; receptor; sex; sex determination; spatiotemporal

PROJECT SUMMARY/ABSTRACT The development and protection of the germline is critical to the fertility and the health of the next generation. My long-term objective is to elucidate the mechanisms, regulation and coordination of embryonic germline processes as an independent investigator. Emerging evidence suggests that the secreted isoprene lipids, retinoic acids and juvenile hormones, have more than one role in the germline lifecycle in vertebrate and invertebrate animals, respectively. Juvenile hormone signaling has been implicated in several aspects adult gametogenesis while retinoic acid has a prominent role in the regulation of meiotic onset timing. However, no shared function for these two isoprenoids have been found to-date despite a high degree of structural similarity, cross-activation capacity, and shared expression patterns during embryonic germline development. Based on a wealth of preliminary studies, the central hypothesis guiding this proposal is that juvenile hormone impacts embryonic germ cell dynamics through a non-classical mechanism and that two functions of retinoic acid and juvenile function in embryonic germ processes are conserved between insects and mammals. Three aims will be completed to test this hypothesis. First, the impact of juvenile hormone will be determined with two approaches. Spatiotemporal juvenile hormone titers will be measured spectrometry-based metabolomics to elucidate the source of juvenile hormone. Then, the impact of juvenile hormone on germ cell dynamics will be determined using live imaging analysis in Drosophila melanogaster embryos. Second, the non-classical, transcription-independent, mechanism of juvenile hormone function will be elucidated by proteomic identification of the juvenile hormone-binding plasma membrane receptors coupled to functional verification, Downstream signaling events will be elucidated using live imaging microscopy in D. melanogaster embryos. Third, the conservation of isoprene lipids on the embryonic germline will be defined by elucidating the impact of retinoic acids on germ cell dynamics in Mus musculus embryos by ex vivo and in vitro necessity and sufficiency assays. Concomitantly, conservation of the post-migratory role for isoprenoids will be examined by defining the role of sex-specific differences in juvenile hormone titers in D. melanogaster germline development. Upon successful completion of this work, the impact, mechanism and conservation of juvenile hormone and retinoic acid on the embryonic germline will be defined. These insights will be important as these bioactive isoprenoids are pervasive in our environment. In fact, juvenile hormone analogues are the active ingredient of many insecticides used throughout the world and have been shown to activate retinoic acid signaling in mammalian cells. Thus, understanding the full impact of these isoprenoids on the embryonic germline is critical and the efforts to gain such understanding align well the general mission of the Eunice Kennedy Shriver National Institute of Child Health and Human Development to ensure every person is born healthy, productive, are free of disease.

项目摘要/摘要 种系的发展和保护对于下一代的生育和健康至关重要。 我的长期目标是阐明胚胎种系的机制，调节和协调 作为独立研究者的过程。新兴的证据表明，分泌的异戊二烯脂质， 视黄酸和青少年激素在脊椎动物的种系生命周期中具有多个作用 无脊椎动物。青少年激素信号传导与成人的多个方面有关 虽然视黄酸在减数分裂开始时机的调节中具有重要作用。但是，不 尽管有高度的结构 相似性，交叉激活能力和胚胎种系发育过程中的共享表达模式。 基于大量初步研究，指导该提议的中心假设是少年激素 通过非古典机制影响胚胎生殖细胞动力学，这是视网膜的两个功能 胚胎生殖过程中的酸和青少年功能在昆虫和哺乳动物之间是保守的。三 目标将完成以检验这一假设。首先，少年激素的影响将用两个 方法。时空少年激素滴度将以光谱法的代谢组为基础 阐明少年激素的来源。然后，少年激素对生殖细胞动力学的影响将是 使用果蝇中的实时成像分析确定。第二，非古典， 蛋白质组学将阐明少年激素功能的转录非依赖性，少年激素功能的机制 鉴定少年激素结合质膜受体，与功能验证相连， 使用D. melanogaster胚胎中的实时成像显微镜将阐明下游信号事件。 第三，将通过阐明的影响来定义胚胎种系上异戊二烯脂质的保护 视体肌肉胚胎的生殖细胞动力学的视黄酸通过体内和体外必要性和 足够的测定。随之而来的是，将检查类吸引力的迁移后作用。 定义性别特异性差异在少年激素滴度中的作用。 发展。成功完成这项工作后，少年的影响，机制和保护 将定义胚胎种系上的激素和视黄酸。这些见解将很重要 生物活性类异戊二烯在我们的环境中普遍存在。实际上，青少年激素类似物是活跃的 全世界使用的许多杀虫剂的成分，已被证明激活视黄酸 哺乳动物细胞中的信号传导。因此，了解这些类异型的全部影响对胚胎 种系至关重要，并且努力使这种理解良好地保持尤尼斯的一般使命 肯尼迪·什里弗（Kennedy Shriver）国家儿童健康与人类发展研究所，以确保每个人出生 健康，富有生产力，没有疾病。