Developmental regulation of the cell cycle machinery

细胞周期机制的发育调控

• 批准号: 10714634
• 负责人: Pablo Andres Lara-Gonzalez
• 金额: $ 34.11万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714634
• 关键词: Abnormal Cell; Address; Aging; Biochemistry; Caenorhabditis elegans; Cancer Etiology; Cell Cycle; Cell Cycle Regulation; Cell Cycle Stage; Cell Differentiation process; Cell Proliferation; Cells; Complex; Cues; Cyclin B; Defect; Development; Disease; Embryonic Development; Equilibrium; Event; Failure; Generations; Genomics; Goals; In Vitro; Malignant Neoplasms; Mitosis; Mitotic; Molecular; Nutrient; Nutritional; Organism; Pathway interactions; Proliferating; Regulation; Research; Signal Transduction; Tissues; Work; cell fate specification; in vivo; insight; prevent; programs; response

PROJECT SUMMARY The development of an organism requires a delicate balance of cell proliferation with cell cycle exit events that necessitates the regulation of the cell cycle machinery to interface with the developmental program. Among critical cell cycle exit events during development are cell differentiation and cell cycle pause, also known as quiescence. The decision to proliferate or exit the cell cycle is influenced by a multitude of factors, including developmental, environmental and nutritional cues. Failures in these decisions are the cause of cancer, as well as developmental abnormalities and aging-related disorders. My overarching goal is to address how the core cell cycle machinery integrates diverse inputs to execute the decision to enter and exit the quiescent state and to couple the cell cycle to cell fate determination during development. My prior work employing C. elegans provided fundamental new insights into the control of cell cycle state transitions in an in vivo context. Using the developing germline, a tissue of utmost importance for the accurate propagation of the genomic information across generations and where cell cycle regulation is tied to nutrient signaling, I uncovered a conserved molecular mechanism that allows for the accumulation of cyclin B to drive entry into mitosis. I also determined how the cell cycle machinery is specialized in different developmental contexts to promote cell proliferation, with particular emphasis on the Cdk1-Cyclin B complex that coordinates mitotic entry and exit events. In this proposal, my group will capitalize on our expertise in cell cycle regulation mechanisms, in vitro biochemistry and developmental analyses to delineate the molecular mechanism by which germline precursors enter into and exit from a non-cannonical form of quiescence at the G2 stage of the cell cycle in response to nutrient signaling, to address how these signals interface with the pathways that regulate entry into mitosis, and to determine how the cell cycle machinery intersects with cell fate specification to promote cell differentiation during embryonic development. This work will drive new understanding of how cell cycle decision points are regulated during development, which could help prevent and/or treat disorders originating from cell proliferation defects.

项目摘要 生物体的发展需要细胞增殖与细胞周期出口事件的微妙平衡， 需要调节细胞周期机械以与发展程序接口。之中 开发过程中关键细胞周期出口事件是细胞分化和细胞周期暂停，也称为 静止。扩散或退出细胞周期的决定受许多因素的影响，包括 发展，环境和营养提示。这些决定中的失败也是癌症的原因 作为发育异常和与衰老有关的疾病。我的总体目标是解决核心如何 单元周期机械集成了各种输入，以执行进入和退出静态状态的决定 将细胞周期与发育过程中的细胞命运确定。我先前雇用秀丽隐杆线虫的工作 在体内环境中，提供了对细胞周期状态过渡的控制的基本新见解。使用 开发种系，这是准确传播基因组信息的最重要的组织 在几代人中以及细胞周期调节与养分信号相关的地方，我发现了一个保守的 分子机制允许聚集细胞周期蛋白B促进有丝分裂。我也确定 细胞周期机械如何在不同的发育环境中专门用于促进细胞增殖，并以 特别强调CDK1-循环B复合物，该复合物协调有丝分裂的进入和退出事件。在此提案中， 我的小组将利用我们在细胞周期调节机制，体外生物化学和 发育分析来描述生殖前体进入并退出的分子机制 从细胞周期的G2阶段的非通风形式的静止形式响应营养信号，到 解决这些信号如何与调节有丝分裂进入的途径接口，并确定如何 细胞周期机械与细胞命运规范相交，以促进胚胎中的细胞分化 发展。这项工作将推动对细胞周期决策点如何调节的新理解 开发，可以帮助预防和/或治疗源自细胞增殖缺陷的疾病。