CAREER: Predicting cell fate from cell history: theory, experiment, and outreach

这项研究项目将使人们更好地理解细胞--所有活着的有机体的基石--如何生长、分裂并将特征传递给其他细胞。就像人类的特征，如身高或眼睛颜色，从父母传给他们的后代一样，细胞也可以显示出可观察到的遗传模式。这个项目的具体目标是了解细胞的遗传特征如何影响其未来的行为；例如，它是否会停止分裂或成为更特殊类型的细胞。因此，这项工作解决了生物学中一个基本的、尚未回答的问题，该问题可能会影响整个生命科学的多个学科。研究目标与社区外联活动紧密结合，旨在教育和吸引不同的学生群体，包括代表人数不足的少数群体。该项目将开发一款在线游戏，在游戏中，来自城市小学的学生将通过追踪细胞随时间推移的图像来为细胞创建“家谱”。学生将在学习细胞生物学基本原理的同时，为每个成功跟踪的细胞获得积分。此外，研究人员将主持一场公开比赛，让当地高中生竞争，利用该项目产生的数据集，开发出最准确的细胞行为模型。因此，这个项目解决了细胞生物学中的一个基本问题，并提供了机会来教授未被充分代表的群体，并利用他们对科学的新兴趣和天赋。这项研究的总体假设是，除了环境线索外，单个细胞的命运强烈地受到该细胞自身寿命内以及其祖先细胞寿命期间发生的一系列事件的影响。通过建立单细胞寿命和血统关系的计算模型，并应用这些模型来定量地理解细胞的个人和家族历史如何影响其命运决定，来追求这一假设。该项目将使用荧光延时显微镜来量化跨越多代细胞的数千个相关细胞的遗传模式。细胞将受到环境压力或发育信号的挑战，单个细胞及其后代的命运将被决定。有了这些数据，数学模型将被用来：(I)了解单个细胞的寿命是如何调节的；(Ii)量化单个细胞的特征是如何遗传的；以及(Iii)确定细胞历史上的分子事件如何决定其命运。该项目专注于两种单细胞特征的遗传模式：DNA双链断裂(通常会减缓细胞周期的进展)；以及典型的多能性因子OCT4的表达(通常会抑制细胞的分化，使其处于多能性状态)。定量预测将通过有针对性的实验扰动来验证。这项工作的成功完成将导致开发一种新的理论框架，以了解细胞历史上发生的关键事件如何塑造其功能反应。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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 lead to a better understanding of how cells -the building blocks of all living organisms- grow, divide, and pass on traits to other cells. Just as human traits, such as height or eye color, are transmitted from parents to their offspring, cells can also show observable patterns of inheritance. The specific goal of this project is to understand how a cell's inherited traits affect its future behavior; for example, whether it will stop dividing or become a more specialized type of cell. As such, this work addresses a fundamental, unanswered question in biology that could impact multiple disciplines across the life sciences. The research goals are deeply integrated with community outreach activities designed to educate and engage a diverse group of students including underrepresented minorities. The project will produce an online game in which students from an urban elementary school will create 'family trees' for cells by tracing images of cells over time. Students will earn points for each successfully tracked cell while learning the basic principles of cell biology. In addition, the investigator will host an open competition in which local high-school students compete to develop the most accurate models of cell behavior using data sets produced by the project. Thus, this project addresses a fundamental problem in cell biology and provides opportunities both to teach underrepresented groups and to draw on their emerging interest in, and talent for, science.The overarching hypothesis of this study is that, in addition to environmental cues, an individual cell's fate is strongly influenced by the sequence of events that occurred both within that cell's own lifetime as well as during the lifetimes of its ancestor cells. This hypothesis will be pursued by developing a computational model of single-cell lifetimes and lineage relationships and applying these models to understand, in quantitative terms, how a cell's individual and family history influences its fate decisions. The project will employ fluorescence time-lapse microscopy to quantify inheritance patterns across thousands of related cells spanning multiple cellular generations. Cells will be challenged with environmental stresses or developmental signals and the fates of individual cells and their offspring will be determined. With these data in hand, mathematical models will be used to: (i) understand how the lifetimes of individual cells are regulated; (ii) quantify how single-cell traits are inherited; and (iii) determine how molecular events in a cell's history determine its fate. The project focuses on the inheritance patterns of two single-cell traits: DNA double-stranded breaks (that generally slow progression through the cell cycle); and expression of a canonical pluripotency factor, OCT4 (that generally inhibits differentiation of cells and keeps them in a pluripotent state). Quantitative predictions will be validated through targeted experimental perturbations. Successful completion of the work will lead to the development of a new theoretical framework for understanding how critical events occurring throughout a cell's history shape its functional responses.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.