The C. elegans Germline: A Test Tube for Cell and Developmental Biology

线虫种系：细胞和发育生物学的试管

• 批准号: 10578828
• 负责人: David Irwin Greenstein
• 金额: $ 44.95万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578828
• 关键词: Address; Affect; Area; Biological Models; Caenorhabditis elegans; Cell Cycle; Cell Nucleus; Cells; Cellular biology; Complex; Congenital Abnormality; Data; Defect; Development; Developmental Biology; Disease; Embryo; Ensure; Ethics; Event; Fertilization; Gametogenesis; Gap Junctions; Genetic; Genetic Models; Germ Cells; Goals; Health; Heart; Human; Infertility; Investigation; Knowledge; Laboratory Organism; Mediating; Meiosis; Modernization; Molecular; Nature; Nematoda; Nuclear; Nuclear Envelope; Nutritional; Oocytes; Oogenesis; Process; Proteins; Regulation; Regulator Genes; Reproduction; Research; Research Proposals; Role; Series; Signal Transduction; Spontaneous abortion; System; Technology; Testing; Translational Regulation; Translations; Tube; Vision; Work; cell behavior; fundamental research; germline stem cells; human disease; insight; intercellular communication; mechanical force; mechanotransduction; neuronal cell body; novel therapeutic intervention; posttranscriptional; programs; reproductive function

SUMMARY/ABSTRACT Overview: Reproduction relies on a complex series of cell fate decisions, cell cycle transitions, and differentiation events, which coordinate the formation and function of gametes with the process of meiosis. A century of research using many experimental organisms, including the nematode Caenorhabditis elegans, defined key intercellular signals regulating germline development, delineated central players in meiosis, and revealed the importance of post-transcriptional gene regulatory mechanisms. Yet, important mechanistic questions remain about how intercellular communication integrates the underlying molecular mechanisms into a coherent germline developmental program. This research proposal addresses several central questions: •How do soma-germline gap junctions orchestrate germline development, coordinate germline developmental subroutines, and integrate nutritional signals to optimize reproduction? •How do intercellular signals and gametic interactions regulate protein translation to enable fertilization and ensure the vitality of the embryo? •Can we exploit the dynamic nature of germline development in which germ cell nuclei move within the gonadal tube to provide broad insights into the cell biology of diseases affecting the nuclear envelope? Goals: The chief goal of our work is to delineate the regulatory networks governing conserved and essential steps in germline development. Our focus will be on three areas: (1) The role of gap junctions in controlling soma-germline interactions; (2) The regulation of protein translation by intercellular signaling during oocyte meiotic maturation and the oocyte-to-embryo transition; and (3) Studies in the C. elegans germline system that provide insights into the cell biology of a class of human diseases affecting the nuclear envelope. In pursuing these goals, we will fill three key gaps in understanding: (i) the nature of the active biomolecules that transit through gap junctions to mediate their many essential reproductive functions; (ii) the function and regulation of a large translational regulatory machine that lies at the heart of the oocyte meiotic maturation decision and the oocyte-to-embryo transition; and (iii) the involvement of nuclear mechanotransduction and endogenous mechanical forces in the origin of diseases affecting the nuclear envelope. Vision: Using the powerful combination of genetic and modern molecular technologies available in C. elegans, we will advance our understanding of germline development, germline stem cell behavior, and oogenesis. In the course of these investigations, we will discover new molecular principles vital to human health and inform the development of novel therapeutic strategies to treat disease. This fundamental research in a genetic model system will generate foundational knowledge for understanding reproduction and the origin of birth defects.

摘要/摘要 概述：繁殖依赖于一系列复杂的细胞命运决策，细胞周期过渡， 和分化事件，将游戏的形成和功能协调 减数分裂的过程。使用许多实验生物的一个世纪研究， 包括线虫秀丽隐杆线虫，定义的关键细胞间信号调节 种系开发，划定了减数分裂中的中心参与者，并揭示了 转录后基因调节机制。然而，重要的机械问题仍然存在 细胞间通信如何将潜在的分子机制整合到相干 种系发展计划。该研究提案解决了几个中心问题： •SOMA-GERMLINE间隙连接如何编排种系开发，协调 种系发育子例程和综合营养信号以优化繁殖？ •相互作用信号和配子相互作用如何调节蛋白质翻译以启用 受精并确保胚胎的活力？ •我们可以利用种系发育的动态性质，其中生殖细胞核移动在内 性腺管为影响核疾病的细胞生物学提供广泛的见解 信封？ 目标：我们工作的主要目标是描述构成的监管网络，并 种系开发的基本步骤。我们的重点将是三个领域：（1）差距的作用 控制SOMA-GERMLINE相互作用的连接； （2）蛋白质的调节 卵母细胞减数分裂成熟期间的细胞间信号转导和翻译 卵母细胞到永远的过渡； （3）在秀丽隐杆线虫种系系统中提供的研究 洞悉影响核包膜的一类人类疾病的细胞生物学。 追求这些目标，我们将填补理解的三个关键空白：（i）活跃的本质 通过间隙连接传输以介导其许多基本复制性的生物分子 功能； （ii）大型翻译的调节机的功能和调节 卵母细胞减数分裂成熟决策的核心和卵母细胞到胚胎过渡；和 （iii）核机械转导和内源性力的参与 影响核包膜的疾病的起源。 视力：使用C中可用的遗传和现代分子技术的强大组合。 秀丽隐杆线，我们将提高我们对种系发育，种系干细胞行为的理解， 和卵子发生。在这些调查过程中，我们将发现新的分子原理 对人类健康至关重要，并为治疗疾病的新型治疗策略提供了发展。 遗传模型系统中的这项基本研究将为 了解繁殖和出生缺陷的起源。