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

该研究项目将有助于更好地了解细胞-所有生物体的组成部分-如何生长，分裂并将特征传递给其他细胞。就像身高或眼睛颜色等人类特征从父母传给后代一样，细胞也可以显示出可观察到的遗传模式。该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一种更特殊的细胞类型。因此，这项工作解决了生物学中一个基本的、悬而未决的问题，可能会影响生命科学的多个学科。研究目标与社区外展活动紧密结合，旨在教育和吸引包括代表性不足的少数民族在内的多样化学生群体。该项目将制作一个在线游戏，在游戏中，来自城市小学的学生将通过追踪细胞随时间的图像来创建细胞的“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，研究人员还将举办一场公开竞赛，让当地高中生竞争，利用该项目产生的数据集开发最准确的细胞行为模型。因此，该项目解决了细胞生物学中的一个基本问题，并提供了机会，既可以教授代表性不足的群体，也可以利用他们对科学的新兴趣和天赋。单个细胞的命运受到细胞自身生命周期内以及细胞生命周期内发生的一系列事件的强烈影响。它的祖先细胞这一假设将通过开发单细胞寿命和谱系关系的计算模型来实现，并应用这些模型来定量了解细胞的个体和家族史如何影响其命运决定。该项目将采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，并将确定单个细胞及其后代的命运。有了这些数据，数学模型将用于：（i）了解单个细胞的寿命是如何调节的;（ii）量化单细胞性状是如何遗传的;（iii）确定细胞历史中的分子事件如何决定其命运。该项目的重点是两个单细胞性状的遗传模式：DNA双链断裂（通常会减缓细胞周期的进展）;和典型多能性因子OCT 4的表达（通常会抑制细胞的分化并使其保持多能性状态）。定量预测将通过有针对性的实验扰动进行验证。这项工作的成功完成将导致一个新的理论框架的发展，了解如何在整个细胞的历史发生的关键事件塑造其功能反应。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.