Project 2

计划2 酵母菌群发育的多尺度时空动力学研究 导论. 在生命系统中，个体的特征，包括对疾病的易感性或对治疗的反应等特征，是由在不同组织尺度上发挥作用的过程的耦合决定的。例如，一个人的DNA序列限制了控制其细胞状态和行为的分子网络，这反过来又决定了多细胞结构的形式和功能。微生物，包括酿酒酵母，传统上被用作在单细胞水平上研究基本细胞过程的模型。然而，单细胞生物可以形成多细胞群落，并分化成专门的结构，使种群受益。在S.酿酒酵母集落（其从单个细胞开始并有丝分裂成为~ 10 × 8]细胞的结构）经历形态学转变，其特征在于集落殖民地表面上复杂的“皱纹”图案（图11）。 这种性状被称为“蓬松”表型。其他人的工作表明，蓬松的酵母菌群拥有许多 微生物生物膜的特性，因此直接与健康和人类疾病相关。在蓬松的蜂群中， 细胞通过细胞外基质和内部中空通道连接，这可能有助于交换营养物质 和废物。虽然有一些证据表明，这种形态发展涉及营养驱动 细胞状态转换，细胞间信号传导，群体感应和细胞死亡，确切的分子和 在许多情况下，这些途径在很大程度上是未知的。 实验系统的重要性：该项目旨在了解细胞如何建立和 维持细胞状态转变的时空模式以形成多细胞结构。在我们的模型（酵母 “蓬松”集落形成）单个细胞分裂，经历一系列代谢和功能转变， 可重复地自组织成10®细胞的复杂结构。通过推进概念上的，计算上的， 和技术挑战，我们将开发一个通用的方法来分析复杂的性状， 形态表型，因此可以应用于各种各样的问题，如身体出生缺陷， 在肿瘤生长过程中发生或血管生成。

Project 2 Multiscale spatial and temporal dynamics of yeast colony development Introduction. In living systems, the characteristics of an individual, including traits such as susceptibility to disease or response to therapy, are determined by the coupling of processes that function at different scales of organization. For example, an individual's DNA sequence constrains the molecular networks that govern its cellular states and behaviors, which in turn determine the form and functions of multi-cellular structures. Microorganisms, including the yeast Saccharomyces cerevisiae, are traditionally used as models for investigating basic cellular processes at the unicellular level. However, unicellular organisms can form multi-cellular communities and differentiate into specialized structures to benefit the population. In some wild isolates of S. cerevisiae colonies (which start from a single cell and divide mitotically to become a structure of -10[8] cells) undergo a morphological transition characterized by complex patterns of"wrinkles" on the colony surface (Fig. 11). This trait is called the "fluffy" phenotype®°. Work by others has shown that fluffy yeast colonies possess many properties of microbial biofilms and are thus directly relevant to health and human disease®'. In fluffy colonies, cells are connected by an extracellular matrix and internal hollow channels, which may help exchange nutrients and waste products. While there is some evidence that this morphological development involves nutrientdriven cell state transitions, cell-cell signaling, quorum sensing and cell death®^, the exact molecules and in many cases the pathways are largely unknown. The importance of the experimental system: This project seeks to understand how cells establish and maintain spatiotemporal patterns of cell state transitions to form multicellular structures. In our model (yeast "fluffy" colony formation) a single cell divides a undergoes a series of metabolic and functional transitions to reproducibly self organize into a complex structure of 10® cells. By advancing the conceptual, computational, and technical challeges below, we will develop a general methodology for analyzing complex traits that exhibit morphological phenotypes and can thus be applied to problems as diverse as physical birth defects during development or angiogenesis during tumor growth.