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Elucidating the network design principles of biological signal processing

阐明生物信号处理的网络设计原理

基本信息

批准号：
10622254
负责人：
Megan N McClean
金额：
$ 40.51万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2028-08-31
项目状态：
未结题

项目摘要

Project Summary Cells live in diverse environments and cellular communities, from the cells in our bodies to single-celled organisms surviving in the soil. 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 external signals to the activity of intracellular effectors, such as transcription factors, to generate an appropriate cellular response or state and how these cell states affect community-level phenotypes. Understanding this signal processing represents a key gap in our knowledge of how healthy and diseased cells make decisions and guide the behavior of cellular communities. Specifically, we ask (1) How do signaling networks transform extracellular signals into appropriate intracellular signals? (2) How are intracellular signals interpreted by the cell to generate appropriate responses? and (3) How do individual cell decisions affect population-level community phenotypes? Our research is focused on understanding signaling specificity and kinetics in the mitogen-activated kinase (MAPK) pathways as well as transcription factor dynamics and subsequent gene expression 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. We use a variety of systems to address the questions outlined in this research proposal including Saccharomyces cerevisiae, the human fugal pathogen Candida albicans, synthetic signaling pathways, and mammalian cell culture. We take a multi-pronged approach that uses 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. And finally, we use the exquisite spatiotemporal control available with light to generate desired states in individual or populations of cells, including fungal biofilms, and ask how this affects community-level phenotypes.

项目摘要细胞生活在不同的环境和细胞群落中，从我们体内的细胞到单细胞在土壤中生存的生物。为了在这些复杂的环境中导航，细胞必须能够感知并对各种信号作出反应。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，处理外部信号并传递信息。我的研究项目集中在了解这些生物网络如何将有关外部信号的信息传递到细胞内效应物，如转录因子，以产生适当的细胞应答或状态，这些细胞状态如何影响群落水平的表型。理解这种信号处理是一个关键我们对健康和患病细胞如何做出决定和指导细胞行为的知识存在差距。社区.具体来说，我们问（1）信号网络如何将细胞外信号转化为适当的信号。细胞内信号？(2)细胞如何解释细胞内信号以产生适当的反应？以及（3）单个细胞的决定如何影响群体水平的群落表型？我们的研究重点是了解丝裂原活化激酶的信号特异性和动力学（MAPK）途径以及转录因子动态和随后的基因表达，环境压力MAP激酶途径从酵母到人类都是保守的，并且控制重要的细胞包括增殖、分化和应激反应的过程。我们使用各种系统来解决这项研究计划中概述的问题包括酿酒酵母，人类真菌病原体，白色念珠菌、合成信号通路与哺乳动物细胞培养。我们多管齐下它使用微流体和光遗传学工具来干扰信号通路，并将这些干扰与联合收割机结合起来，数学建模，以了解信号通路的不同特性，包括带宽和串扰，使它们能够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物（例如转录因子）的动态，并询问这些不同的效应物动态如何产生细胞反应。最后，我们利用光的精妙时空控制，在单个或细胞群体中产生所需的状态，包括真菌生物膜，并询问这如何影响社区水平的表型。