Bilateral NSF/BIO-BBSRC: The design logic of Hedgehog-based pattern formation.

生物学的一个关键挑战是了解细胞如何相互交流和反应。这在胚胎发育中尤其重要，因为细胞通讯负责创造模式，这些模式是功能器官形成的模板。 该项目是加州理工学院（美国）和弗朗西斯克里克研究所（英国）的研究人员之间的合作，研究人员将使用一种新的定量方法在单细胞水平上研究Sonic Hedgehog通路（一种在发育中非常重要的信号通路）中的信号传导，该信号传导导致模型组织培养系统中的神经模式。这些结果将阐明控制细胞命运决定和组织模式精确性的机制 在发展中 脊髓 这些 这些原则的广泛影响 很可能 是相关 以了解参与不同发育过程的其他信号通路。该项目还将为培养生物学和计算接口的研究生提供一个独特的机会。在胚胎发育期间和对损伤的反应中，组织必须建立或重新建立特定细胞类型的精确空间排列。 组织模式化的常见策略涉及形态发生素;局部产生的分泌分子，其扩散以形成浓度梯度。这些梯度为组织提供位置信息，用于调节控制细胞命运决定的空间特异性基因。此外，形态发生素还调节下游的 目标 基因 的 可以 影响 的 成形素 运动， 细胞内 信号转导和靶基因表达的阐述。这为形态发生器提供了一种生成梯度和位置信息的手段，该梯度和位置信息具有特定于背景的形状和动力学，以指导组织图案形成。在理解控制形态发生蛋白表达的途径的结构方面的一个关键限制是缺乏胚胎组织中的直接读出和控制。为了解决这一不足，本研究计划将联合收割机结合新的定量单细胞和组织工程方法在明确的细胞模型系统。该项目的目的是了解产生Hedgehog（SHH）通路的动力学和基因反应的设计原理，该通路参与不同的发育过程，特别是神经系统的模式化。以下关于形态发生素介导的组织图案化的基本问题将被解决：（1）形态发生素梯度的动力学是如何产生和控制的？(2)单个细胞中的基因如何将形态发生素编码的定量、动态信息解释为离散的细胞命运？(3)波动或“噪音”如何限制图案的精确性，细胞如何克服这些限制？ 该项目的更广泛影响将是将形态发生动力学与细胞命运决策联系起来的预测性定量模型，这为胚胎和生物体中众多Shh依赖性过程提供了见解，也使研究人员能够控制和重新利用Shh信号传导，以便在制造的组织中设计图案。该项目也将为培养生物学和计算接口的研究生提供一个独特的机会。这个美国/英国合作项目得到了美国国家科学基金会和英国生物技术和生物科学研究理事会的支持。

A key challenge in biology is to understand how cells communicate and respond to one another. This is particularly important in developing embryos where cell communication is responsible for creating the patterns which are the template for the formation of functioning organs. In this project which is a collaboration between researchers at the California Institute of Technology (US) and the Francis Crick Institute (UK), investigators will use a novel quantitative approach to examine signaling in the Sonic Hedgehog pathway (a signaling pathway very important in development) at the single cell level that leads to neural patterning in a model tissue culture system. The results will elucidate the mechanism that controls the precision of cell fate decision and tissue patterning in the developing spinal cord. These broader impacts of these principles are likely to be relevant for understanding other signaling pathways involved in diverse developmental processes. This project will also provide a unique opportunity for training graduate students at the interface of biology and computation.During embryonic development and in response to injury, tissues must establish, or re-establish, precise spatial arrangements of specific cell types. A common strategy of tissue patterning involves morphogens; locally produced, secreted molecules that diffuse to form concentration gradients. These gradients provide the tissue with positional information that is used to regulate spatially specific genes controlling cell fate decisions. Moreover, morphogens also regulate the downstream target genes that can affect the morphogen movement, intracellular signal transduction and the elaboration of target gene expression. This provides a means for morphogens to generate gradients and positional information with context-specific shapes and dynamics to instruct tissue pattern formation. A key limitation in understanding the architecture of pathways that control morphogen expression has been the lack of direct readout and control in embryonic tissues. To address this deficiency, this research project will combine novel quantitative single- cell and tissue engineering approaches in well-defined cellular model systems. The aim of this project is to understand the design principles that produce the dynamics and gene responses of the Hedgehog (SHH) pathway, which are involved in diverse developmental processes, in particular patterning the neural system. The following fundamental questions about morphogen-mediated tissue patterning will be addressed: (1) How are the dynamics of morphogen gradients generated and controlled? (2) How do the genes in individual cells interpret the quantitative, dynamic information encoded by morphogens into discrete cell fates? (3) How do fluctuations, or "noise", limit the precision of patterning, and how do cells overcome these limitations? A broader impact of this project will be predictive, quantitative models connecting morphogen dynamics to cell fate decision-making, which provides insights into numerous Shh-dependent processes in embryos and organisms, and also enables researchers to control and repurpose Shh signaling in order to engineer patterning in manufactured tissues. This project will also provide a unique opportunity for training graduate students at the interface of biology and computation.This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council.