Excitability in Dictyostelium Development

盘基网柄菌发育的兴奋性

基本信息

批准号：
9064777
负责人：
David Jason Schwab
金额：
$ 12.45万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9064777
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 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 condensed matter physics extracellular insight intercellular communication lymph nodes migration mutant neutrophil professor quorum sensing research study response simulation skills slug theories

项目摘要

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（申请人提供）：哪些基本机制是发展的基础，我们如何操纵，破坏或纠正它们？我建议研究Dictyostelium Discoideum的集体行为 - 一种用于细胞 - 细胞信号传导的经典模型生物 - 重点是单细胞动力学如何影响并引起聚集体的行为。在饥饿期间，Dictyostelium细胞定期分泌化学吸收剂营，从而诱导其他细胞中的cAMP产生。结果是波浪般的信号继电器，最终是细胞聚集。从单细胞到多细胞寿命的过渡为利用我的凝结物理学背景来解决生物学的基本问题提供了理想的系统。在普林斯顿，我将与托马斯·格雷戈尔（Thomas Gregor）的实验室密切合作，后者开发了第一个细胞内营地集中注意力的记者。他们的定量实验为将单个细胞的行为与随之而来的人群的命运联系起来提供了独特的机会。我的导师Ned Wingreen的指导是细菌趋化性，梯度感应和细胞 - 细胞通信的专家，将是宝贵的资源。通过分析定量单细胞实验，我开发了一个对细胞外cAMP的单细胞响应的模型。我的初步研究表明，每个细胞都表现为一种令人兴奋的系统（一个很好的例子是尖峰神经元）。我将把这个模型扩展到研究通过CAMP扩散介导的集体空间动力学。在初步研究中，我考虑了一种“平均场”情况，例如在混合良好的灌注室中，发现了有趣的动态群体感应转变。为了包括空间动力学，我将首先构建一个空间梯度传感的模型 - 统一兴奋性，适应性和方向传感的概念 - 由Gregor Lab进行的基于微流体的实验引导。使用该模型，我将通过趋化细胞的模拟定量地重现聚集。我将比较通过土墩中心的大小和空间分布来衡量的聚合保真度与缺乏激发动力学的其他趋化机制。然后，我将探索破坏忠实聚集的方法，并对可以在Gregor Lab中进行测试的各种Dictyostelium突变体的行为进行预测。回答本提案中的问题需要在使用我的背景凝结物理学理论与复杂生物系统的细节之间保持适当的平衡。因此，拟议的项目是我过渡成为在定量生物学领域工作的独立研究人员的理想选择 - 这将使我能够利用自己的既定技能并开发新技能。由于我的导师的指导，内德·温雷恩（Ned Wingreen）和托马斯·格雷戈尔（Thomas Gregor）教授，以及更大的定量生物学家社区，普林斯顿的环境都为有效的独立研究员提供了理想的环境。