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.

摘要/摘要 概述：繁殖依赖于一系列复杂的细胞命运决定、细胞周期转变、 和分化事件，协调配子的形成和功能 一个世纪以来使用许多实验生物进行的研究， 包括线虫秀丽隐杆线虫，定义了关键的细胞间信号调节 种系发育，描绘了减数分裂的核心参与者，并揭示了减数分裂的重要性 然而，转录后基因调控机制仍然存在重要的机制问题。 细胞间通讯如何将潜在的分子机制整合成连贯的 该研究提案解决了几个核心问题： •体细胞-种系间隙连接如何协调种系发育、协调 种系发育子程序，并整合营养信号以优化繁殖？ •细胞间信号和配子相互作用如何调节蛋白质翻译以实现 受精并保证胚胎的活力？ •我们能否利用生殖细胞核在生殖细胞内移动的生殖系发育的动态性质？ 性腺管为影响核疾病的细胞生物学提供了广泛的见解 信封？ 目标：我们工作的主要目标是划定管理保护和保护物种的监管网络。 我们的重点将放在三个领域：（1）间隙的作用。 控制体-种系相互作用的连接；（2）蛋白质的调节 卵母细胞减数分裂成熟过程中细胞间信号转导的翻译 卵母细胞到胚胎的转变；以及（3）线虫种系系统的研究，该系统提供了 对影响细胞核的一类人类疾病的细胞生物学的见解。 为了实现这些目标，我们将填补三个关键的理解空白：(i) 主动行动的本质 通过间隙连接转运以介导许多重要生殖的生物分子 功能；（ii）大型翻译调节机器的功能和调节 卵母细胞减数分裂成熟决策和卵母细胞向胚胎转变的核心； (iii) 核机械传导和内源性机械力参与 影响核膜的疾病的起源。 愿景：利用 C 中可用的遗传和现代分子技术的强大组合。 线虫，我们将加深对生殖系发育、生殖系干细胞行为的理解， 在这些研究过程中，我们将发现新的分子原理。 对人类健康至关重要，并为治疗疾病的新治疗策略的开发提供信息。 这项遗传模型系统的基础研究将为以下领域提供基础知识： 了解生殖和出生缺陷的起源。