Excitability in Dictyostelium Development

盘基网柄菌发育的兴奋性

• 批准号: 8534792
• 负责人: David Jason Schwab
• 金额: $ 12.39万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534792
• 关键词: Accounting; Address; Amoeba genus; Animal Model; Bacteria; Behavior; Biology; Cell Aggregation; Cell Communication; Cell Signaling Process; Cell model; Cells; Cellular Structures; Characteristics; Chemotactic Factors; Chemotaxis; Communities; Cooperative Behavior; Coupled; Cues; Cyclic AMP; Data; Development; Dictyostelium; Dictyostelium discoideum; Diffusion; Down-Regulation; Elements; Embryonic Development; Environment; Equilibrium; Eukaryota; Eukaryotic Cell; Exhibits; Fluorescence Resonance Energy Transfer; Freedom; Goals; Heart; Individual; Lead; Life; Link; Measures; Mediating; Membrane; Mentors; Microfluidics; Microscopic; Modeling; Modification; Molecular; Nature; Neurons; Pattern; Performance; Perfusion; Pharmacotherapy; Phenotype; Physics; Physiologic pulse; Population; Production; Property; Reporter; Research; Research Personnel; Resources; Signal Pathway; Signal Transduction; Social Development; Spatial Distribution; Staging; Starvation; Stimulus; System; Testing; Tissues; Training; Up-Regulation; Work; base; behavior prediction; biological systems; complex biological systems; extracellular; insight; intercellular communication; lymph nodes; migration; mutant; neutrophil; professor; quorum sensing; research study; response; simulation; skills; slug; theories

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.

描述（由申请人提供）：发展的基础是什么基本机制，我们如何操纵，破坏或纠正它们？我建议研究的集体行为的Dictyosteelium discoideum -一个经典的模式生物细胞-细胞信号-专注于如何单细胞动力学的影响，并引起的行为的聚集。在饥饿期间，网骨藻细胞周期性地分泌化学引诱物cAMP，诱导其他细胞产生cAMP。其结果是一个波浪状的信号中继，并最终，蜂窝聚合。这种从单细胞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学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报告基因。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最终命运联系起来。 我的导师内德·温格林（Ned Wingreen）是细菌趋化性、梯度感应和细胞间通讯方面的专家，他的指导将是一个无价的资源。通过对定量单细胞实验的分析，我建立了一个单细胞对细胞外cAMP反应的模型。我的初步研究表明，每个细胞都表现为一个可兴奋的系统（一个主要的例子是尖峰神经元）。我将扩展这个模型来研究集体空间动态介导的cAMP的扩散。在初步研究中，我考虑了一个“平均场”的情况，在一个良好的混合灌注室，发现一个有趣的动态群体感应过渡。为了包括空间动力学，我将首先构建一个空间梯度传感模型-统一兴奋性，适应性和方向感测的概念-由Gregor实验室进行的基于微流体的实验指导。有了这个模型，我将通过模拟趋化细胞来定量地再现聚集。我将比较聚集保真度，衡量的大小和丘中心的空间分布，对其他趋化机制缺乏兴奋的动力学。然后，我将探索破坏忠实聚集的方法，并预测可以在Gregor实验室测试的各种网囊藻突变体的行为。在这个提案中提出的问题需要在利用我在凝聚态物理理论方面的背景和参与复杂生物系统的细节之间取得正确的平衡。因此，拟议的项目是理想的，我的过渡，成为一个独立的研究人员在定量生物学领域的工作，它将允许我使用我的既定技能，并开发新的。普林斯顿大学的环境，由于我的导师内德·温格林教授和托马斯·格雷戈尔教授的指导，以及更广泛的定量生物学家社区，为我发展成为一名有效的独立研究者提供了理想的环境。