Excitability in Dictyostelium Development

描述（由申请人提供）：发展背后的基本机制是什么？我们如何操纵、破坏或纠正它们？我建议研究盘状盘基骨的集体行为-细胞-细胞信号传导的经典模式生物-重点关注单细胞动力学如何影响和引起集体行为。在饥饿期间，盘基骨柱细胞周期性地分泌化学引诱剂cAMP，诱导其他细胞产生cAMP。其结果是一个波状信号中继，并最终实现细胞聚集。这种从单细胞生命到多细胞生命的转变提供了一个理想的系统，可以利用我在凝聚态物理方面的背景来解决生物学中的一个基本问题。在普林斯顿，我将与托马斯·格雷戈尔的实验室密切合作，该实验室开发了第一个细胞内cAMP浓度的FRET报告器。他们的定量实验提供了一个独特的机会，将单个细胞的行为与群体的命运联系起来。

DESCRIPTION (provided by applicant): What basic mechanisms underlie development and how can we manipulate, disrupt, or correct them? I propose to study the collective behavior of Dictyostelium discoideum - a classic model organism for cell-cell signaling - focusing on how single-cell dynamics influence and give rise to the behavior of the aggregate. During starvation, Dictyostelium cells periodically secrete the chemoattractant cAMP, inducing production of cAMP in other cells. The result is a wavelike signal relay, and, ultimately, cellular aggregation. This transition from single-celled to multicellular life provides an ideal system to utilize my background in condensed matter physics to address a fundamental question in biology. At Princeton, I will collaborate closely with Thomas Gregor's lab, which developed the first FRET reporter of intracellular cAMP concentration. Their quantitative experiments provide a unique opportunity to connect the behavior of individual cells with the consequent fate of the population. The guidance of my mentor Ned Wingreen, an expert in bacterial chemotaxis, gradient sensing, and cell-cell communication, will be an invaluable resource. Through analysis of quantitative single-cell experiments, I have developed a model of the single-cell response to extracellular cAMP. My preliminary studies indicate that each cell behaves as an excitable system (a prime example is a spiking neuron). I will extend this model to study collective spatial dynamics mediated by diffusion of cAMP. In preliminary studies, I considered a "mean-field" situation, as in a well-mixed perfusion chamber, finding an intriguing dynamical quorum-sensing transition. To include spatial dynamics, I will first construct a model of spatial gradient sensing - unifying the concepts of excitability, adaptation, and directional sensing - guided by microfluidics-based experiments performed by the Gregor Lab. With this model, I will quantitatively reproduce aggregation through simulations of chemotactic cells. I will compare aggregation fidelity, measured by the size and spatial distribution of mound centers, against other chemotaxis mechanisms lacking excitable dynamics. I will then explore ways to disrupt faithful aggregation and make predictions for the behavior of various Dictyostelium mutants that can be tested in the Gregor Lab. Answering the questions in this proposal requires the right balance between using my background in condensed matter physics theory and engaging with the details of a complex biological system. The proposed project is therefore ideal for my transition to become an independent researcher working in the field of quantitative biology-it will allow me to use my established skills and to develop new ones. The environment at Princeton, both due to the guidance of my mentors, Professors Ned Wingreen and Thomas Gregor, and the greater community of quantitative biologists, provides an ideal setting to develop into an effective independent investigator.