Elucidating the network design principles of biological signal processing

阐明生物信号处理的网络设计原理

• 批准号: 10174953
• 负责人: Megan N McClean
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174953
• 关键词: Address; Animal Model; Awareness; Biological; Cell physiology; Cells; Complex; Decision Making; Disease; Environment; Human; Kinetics; Knowledge; Microbe; Microfluidics; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Organism; Pathway interactions; Phosphotransferases; Process; Property; Proteins; Regulation; Research; Saccharomyces cerevisiae; Saccharomycetales; Signal Pathway; Signal Transduction; Soil; Specificity; Stimulus; Stress; System; Yeasts; biological adaptation to stress; design; experimental study; extracellular; mathematical model; optogenetics; programs; response; sensor; signal processing; technology development; tool; transcription factor

Project Summary Cells live in diverse environments, from the cells in our bodies to single-celled organisms surviving in the soil. In order to navigate these complex environments, cells must be able to sense and respond to a variety of signals. This is done through biological signaling pathways, consisting of sensors and interacting proteins, which process external signals and transmit information. My research program focuses on understanding how these biological networks transmit information about the environment to the activity of intracellular effectors, such as transcription factors, to generate an appropriate cellular response or state. Understanding this signal processing represents a key gap in our knowledge of how healthy and diseased cells make decisions in response to stimuli. Specifically, we ask (1) How do signaling networks transform extracellular signals into appropriate intracellular signals? and (2) How are intracellular signals interpreted by the cell to generate appropriate responses? My research uses Saccharomyces cerevisiae, or budding yeast, as a model organism for addressing these questions in biological signal processing. Budding yeast exists as a unicellular microbe and therefore must be exquisitely aware of its environment in order to survive and compete with neighboring cells. Our research is focused on understanding signaling specificity and kinetics in the mitogen-activated kinase (MAPK) pathways as well as transcription factor regulation in response to environmental stress. MAP kinase pathways are conserved from yeast to humans and control vital cellular processes including proliferation, differentiation, and stress response. Furthermore, we have developed and continue to develop exquisite tools for controlling and perturbing biological networks in Saccharomyces cerevisiae, making this an ideal system in which to address the aforementioned questions. We take a multi-pronged approach. We develop microfluidic and optogenetic tools to perturb signaling pathways and combine these perturbations with mathematical modeling to understanding how different properties of signaling pathways, including bandwidth and crosstalk, allow them to appropriately transform their input signals. Furthermore, we use these tools to drive dynamics of intracellular effectors, such as transcription factors, and ask how these different effector dynamics generate cellular responses.

项目摘要 细胞生活在不同的环境中，从我们体内的细胞到土壤中生存的单细胞生物。 为了在这些复杂的环境中导航，细胞必须能够感知和响应各种各样的信号。 信号.这是通过生物信号通路完成的，由传感器和相互作用的蛋白质组成， 其处理外部信号并传输信息。我的研究项目集中在了解 这些生物网络将关于环境的信息传递给细胞内效应物的活性， 例如转录因子，以产生适当的细胞应答或状态。理解这个信号 处理代表了我们对健康和病变细胞如何做出决策的知识中的一个关键差距， 对刺激的反应。具体来说，我们问（1）信号网络如何将细胞外信号转化为 合适的细胞内信号？以及（2）细胞如何解释细胞内信号以产生 适当的回应？ 我的研究使用酿酒酵母，或芽殖酵母，作为解决这些问题的模式生物。 生物信号处理中的问题。芽殖酵母作为单细胞微生物存在，因此必须 对周围环境有着敏锐的感知，以便生存并与邻近的细胞竞争。我们的研究是 专注于理解丝裂原活化激酶（MAPK）通路中的信号特异性和动力学 以及响应环境胁迫的转录因子调节。MAP激酶途径是 从酵母到人类都是保守的，控制着重要的细胞过程，包括增殖、分化和 应激反应此外，我们已经开发并将继续开发用于控制和 扰乱酿酒酵母中的生物网络，使其成为解决 上述问题。 我们采取多管齐下的方法。我们开发微流体和光遗传学工具来干扰信号传导 联合收割机将这些扰动与数学建模相结合， 信号通路的特性，包括带宽和串扰，使它们能够适当地转换它们的 输入信号。此外，我们使用这些工具来驱动细胞内效应物的动力学，例如转录 因子，并询问这些不同的效应动力学如何产生细胞反应。