Cell Cycle Regulation In Oogenesis

卵子发生中的细胞周期调控

• 批准号: 10266481
• 负责人: MARY A LILLY
• 金额: $ 155.84万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266481
• 关键词: Animal Model; Animals; Cell Cycle; Cell Cycle Regulation; Complex; Congenital Abnormality; Defect; Development; Drosophila genus; Drosophila melanogaster; Event; Female; Gametogenesis; Genome Stability; Germ Cells; Goals; Growth; Homeostasis; Human; Laboratories; Maintenance; Meiosis; Meiotic Prophase I; Metabolic; Metabolism; Modeling; Oocytes; Oogenesis; Pathway interactions; Protocols documentation; Reagent; Recovery; Regulation; Reproductive Biology; Reproductive Medicine; Role; Signal Pathway; Spontaneous abortion; Stress; Work; chromosome missegregation; egg; event cycle; hormonal signals; in vivo; inhibitor/antagonist; insight; interest; member; novel; oocyte quality; programs; repaired

We are interested in understanding how metabolism influences oocyte development and the maintenance of oocyte quality. Over the last four years my laboratory has used studies of two TORC1 regulators, GATOR1 and GATOR2, to explore the role of metabolism in the regulation of meiotic progression in the model organism Drosophila melanogaster. This work has provided insight into the critical role of TORC1 in the regulation of meiotic progression and germline genome stability during the early meiotic cycle. Moreover, our work has provided novel insights into the fundamental role of the GATOR1 and GATOR2 complexes in the regulation of TORC1 activity and endomembrane dynamics in metazoans. Currently, our work in Drosophila represents one of the few in vivo examinations of GATOR2 function in a multicellular animal. Importantly, our work challenges several predictions of the prevailing model of TORC1 regulation by the GATOR complex. Most notably, our studies in Drosophila suggest that multiple members of the GATOR2 complex function primarily in the recovery from stress and may not be generally required for metabolic homeostasis. Thus, we propose that the current model for TORC1 regulation needs to be refined. The major objectives of this proposal are: (1) To develop reagents and protocols to examine in vivo, the dynamic regulation of TORC1 regulators at the subcellular level. (2) To obtain a mechanistic understanding of how the GATOR2 complex controls TORC1 activity through the regulation of the TORC1 inhibitors GATOR1 and TSC. (3) To define how TORC1 activity controls specific steps in meiotic progression and oocyte development including oocyte growth, the repair of meiotic double-stranded breaks and the assembly of the prophase I meiotic spindle. These studies will enhance our understanding of the pathways that control meiotic progression and gametogenesis and will provide basic insights into the regulation of metabolism in metazoans.

我们有兴趣了解新陈代谢如何影响卵母细胞的发展和卵母细胞质量的维持。在过去的四年中，我的实验室使用了对两个TORC1调节剂Gator1和Gator2的研究来探索代谢在模型有机体果蝇果蝇中的减数分裂进展中的作用。这项工作为TORC1在减数分裂周期期间的减数分裂进展和种系基因组稳定性调节中的关键作用提供了深入的了解。 此外，我们的工作为Gator1和Gator2复合物在TORC1活性和后生动力学的内膜动力学调节中的基本作用提供了新的见解。当前，我们在果蝇中的工作代表了多细胞动物中Gator2功能的少数体内检查之一。重要的是，我们的工作挑战了鳄鱼综合体对TORC1调节的主要模型的几个预测。最值得注意的是，我们在果蝇中的研究表明，Gator2复合物的多个成员主要在从压力中恢复中起作用，通常不需要代谢稳态。因此，我们建议需要完善TORC1调节的当前模型。该提案的主要目标是：（1）开发试剂和协议以在体内检查，这是亚细胞级别的TORC1调节剂的动态调节。 （2）获得对Gator2复合物如何通过调节TORC1抑制剂Gator1和TSC来控制TORC1活性的机械理解。 （3）定义TORC1活动如何控制减数分裂进程和卵母细胞发育的特定步骤，包括卵母细胞生长，减数分裂双链断裂的修复以及预言I Meiotic Spindle的组装。这些研究将增强我们对控制减数分裂进程和配子发生的途径的理解，并将为中转的代谢调节提供基本见解。