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: 10328427
• 负责人: David Irwin Greenstein
• 金额: $ 25.46万
• 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/10328427
• 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; Foundations; Gametogenesis; Gap Junctions; Genetic; Genetic Models; Genetic Transcription; 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; Study models; 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; 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.

总结/摘要 概述：生殖依赖于一系列复杂的细胞命运决定，细胞周期转换， 和分化事件，协调配子的形成和功能， 减数分裂的过程一个世纪的研究使用了许多实验生物， 包括秀丽隐杆线虫，定义了调节 生殖系发育，描绘了减数分裂的中心参与者，并揭示了 转录后基因调控机制。然而，重要的机械问题仍然存在， 细胞间通讯如何将潜在的分子机制整合成一个连贯的 生殖系发育计划本研究提案涉及几个核心问题： ·体细胞-生殖系间隙连接如何协调生殖系发育， 生殖系发育子程序，并整合营养信号，以优化生殖？ ·细胞间信号和配子相互作用如何调节蛋白质翻译， 受精和确保胚胎的活力？ ·我们能否利用生殖细胞核在生殖细胞内移动的动态特性 性腺管，以提供广泛的见解，细胞生物学的疾病，影响核 信封？ 目标：我们工作的主要目标是描绘管理保守和 生殖细胞发育的关键步骤。我们的重点将放在三个方面：（1）差距的作用 控制体细胞-生殖系相互作用的连接;（2）蛋白质的调节 在卵母细胞减数分裂成熟过程中通过细胞间信号转导进行翻译， 卵母细胞向胚胎转化的研究; elegans生殖系系统， 深入了解一类影响核膜的人类疾病的细胞生物学。在 为了实现这些目标，我们将填补三个关键的理解空白：（一）积极的性质 生物分子通过缝隙连接来介导它们的许多基本生殖过程， （二）一个大型翻译调节机器的功能和调节， 在卵母细胞减数分裂成熟决定和卵母细胞到胚胎过渡的核心;和 (iii)核机械力转导和内源性机械力参与了细胞的运动， 影响核膜的疾病起源。 愿景：利用基因和现代分子技术的强大组合，在C。 elegans，我们将推进我们对生殖系发育，生殖系干细胞行为， 和卵子发生在这些研究的过程中，我们将发现新的分子原理 这对人类健康至关重要，并为治疗疾病的新治疗策略的开发提供信息。 遗传模型系统中的基础研究将产生基础知识， 了解生殖和出生缺陷的起源。