Developmental regulation of the cell cycle machinery

项目摘要 生物体的发育需要细胞增殖与细胞周期退出事件的微妙平衡， 需要调节细胞周期机制，以与发育程序相结合。之间 在发育过程中，关键的细胞周期退出事件是细胞分化和细胞周期暂停，也称为细胞周期暂停。 安静增殖或退出细胞周期的决定受到多种因素的影响，包括 发育、环境和营养线索。这些决定的失败也是癌症的原因 发育异常和衰老相关疾病。我的首要目标是解决 细胞周期机制整合不同的输入以执行进入和退出静止状态的决定， 在发育过程中将细胞周期与细胞命运决定相结合。我以前的工作是用C。elegans 提供了基本的新的见解控制细胞周期状态转换在体内的情况下。使用 发育生殖系，这是一种对基因组信息的准确传播至关重要的组织 在细胞周期调控与营养信号联系的情况下，我发现了一个保守的 允许细胞周期蛋白B积累以驱动进入有丝分裂的分子机制。我还决定 细胞周期机制如何在不同的发育环境中专门化以促进细胞增殖， 特别强调Cdk 1-细胞周期蛋白B复合物，其协调有丝分裂进入和退出事件。在这一提议中， 我的团队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，以描绘生殖系前体进入和退出的分子机制 从响应营养信号的细胞周期G2期的非典型静止形式，到 解决这些信号如何与调节进入有丝分裂的途径相互作用，并确定这些信号如何与细胞分裂信号相互作用。 细胞周期机制与细胞命运特化交叉以促进胚胎期细胞分化 发展这项工作将推动对细胞周期决策点如何在细胞周期中调节的新理解。 本发明提供了一种用于促进细胞发育的药物组合物，其可以帮助预防和/或治疗源自细胞增殖缺陷的病症。

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.