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: 10580291
• 负责人: Megan N McClean
• 金额: $ 20.55万
• 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/10580291
• 关键词: Address; Anatomy; Animal Model; Awareness; Biological; Cell physiology; Cells; Chromatin Remodeling Factor; Complex; Decision Making; Disease; Environment; Enzymes; Equipment; Fibrinogen; Gatekeeping; Gene Expression; Human; Kinetics; Knowledge; Libraries; Light; Measurement; Metabolic; Microbe; Microfluidics; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Nuclear; Organism; Pathway interactions; Phosphotransferases; Process; Property; Proteins; Regulation; Research; Saccharomyces cerevisiae; Saccharomycetales; Series; Signal Pathway; Signal Transduction; Soil; Specificity; Stimulus; Stress; Structure; System; Time; Translating; Work; Yeasts; biological adaptation to stress; design; experimental study; extracellular; interest; mathematical model; optogenetics; programs; promoter; rapid technique; 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 understand 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。在……里面 为了适应这些复杂的环境，细胞必须能够感知和响应各种信号。 这是通过生物信号通路完成的，生物信号通路由传感器和相互作用的蛋白质组成，它们在 外部信号和传输信息。我的研究项目重点是了解这些生物 网络将有关环境的信息传递给细胞内效应器的活动，如转录 因素，以产生适当的细胞反应或状态。理解这种信号处理代表着 这是我们对健康和患病细胞如何对刺激做出决定的知识中的一个关键差距。具体来说， 我们问(1)信令网络如何将细胞外信号转换为适当的细胞内信号？和 (2)细胞如何解释细胞内的信号以产生适当的反应？ 我的研究使用酿酒酵母，或萌芽酵母，作为解决这些问题的模式生物 生物信号处理中的问题。发芽酵母是以单细胞微生物的形式存在的，因此必须 敏锐地意识到它所处的环境，以便生存并与邻近的细胞竞争。我们的研究是 重点了解丝裂原活化激酶(MAPK)通路中的信号特异性和动力学 以及转录因子对环境胁迫的调控。MAP激酶途径有 从酵母到人类的保守，并控制重要的细胞过程，包括增殖，分化和 压力反应。此外，我们已经并将继续开发精致的工具来控制和 扰乱酿酒酵母中的生物网络，使其成为一个理想的解决系统 前面提到的问题。 我们采取多管齐下的方法。我们开发微流控和光遗传工具来扰乱信号通路 并将这些扰动与数学建模相结合，以了解信号的不同属性如何 路径，包括带宽和串扰，允许它们适当地转换其输入信号。 此外，我们使用这些工具来驱动细胞内效应器的动力学，如转录因子，以及 问问这些不同的效应器动力学是如何产生细胞反应的。