Toward a revised model of the cell cycle that captures reversible and irreversible arrest

这个研究项目将扩展我们对细胞如何经历停滞的认识，在这种状态下，细胞仍然活着，但暂时或永久地停止分裂。细胞周期的教科书模型描述了一个单一的捕获状态，但基本上没有说明这个状态是否由多个捕获状态组成；细胞如何进入或退出这些状态；以及细胞如何从可逆阻滞转变为不可逆阻滞。该项目将定义控制可逆和不可逆阻滞的分子步骤，并揭示细胞周期的灵活性。这些研究目标与两项社区外展活动深度结合，这两项活动将吸引不同群体的学生和科学家。在与达勒姆公立学校建立长期合作关系的基础上，七年级的学生将学习细胞周期的基础知识以及进行显微镜检查所需的技术技能。该项目还利用了与北卡罗来纳大学“自闭症和相关沟通障碍儿童的治疗和教育”项目的现有合作伙伴关系，聘请了两名神经多样性个体对细胞周期数据进行图像分析。该项目的第一个目标是研究可逆的细胞周期阻滞，具体目标是确定细胞如何在静止（细胞周期阻滞的暂时状态）后恢复G1期并进入S期。扰动实验将测试CDKs/细胞周期蛋白的积累压倒促阻滞因子以促进细胞周期重新进入的机制。第二个目的是研究控制不可逆细胞周期阻滞的机制，这是一种通常与细胞衰老相关的表型。延时成像和计算模型将确定控制过渡到永久停止的分子步骤的精确序列。对G1和G2监管机构的系统性干扰，预计将使逮捕的持久性有所放松。这些研究目标的成功完成将填补细胞周期如何组织和调节的关键知识空白。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This research project will extend our knowledge of how cells undergo arrest, a state in which they are still alive but stop dividing—either temporarily or permanently. The textbook model of the cell cycle describes a single state of arrest but is mostly silent on whether this state consists of multiple arrested states; how cells may enter or exit these states; and how cells transition from reversible to irreversible arrest. This project will define the molecular steps that govern reversible and irreversible arrest and reveal how flexible the cell cycle is. These research objectives are deeply integrated with two community outreach activities that will engage a diverse group of students and scientists. Building on a long-term partnership with Durham public schools, seventh-grade students will learn the fundamentals of the cell cycle as well as the technical skills needed to perform microscopy. The project also draws on an existing partnership with the University of North Carolina's 'Treatment and Education of Autistic and Related Communication Handicapped Children' Program to employ two neurodiverse individuals to perform image analysis of cell cycle data.The first aim of this project focuses on reversible cell cycle arrest with the specific goal of determining how cells resume G1 and enter S phase following quiescence, a temporary state of cell cycle arrest. Perturbation experiments will test mechanisms by which the accumulation of CDKs/cyclins overwhelms pro-arrest factors to promote cell cycle re-entry. The second aim investigates mechanisms controlling irreversible cell cycle arrest, a phenotype commonly associated with cellular senescence. Time-lapse imaging and computational modeling will identify the precise sequence of molecular steps governing transition to permanent arrest. Systematic perturbation of G1 and G2 regulators are expected to relax the permanency of arrest. Successful completion of these research objectives will fill critical knowledge gaps in how the cell cycle is organized and regulated.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.