Understanding Mechanisms of Robust Information Processing by NF-kappaB

了解 NF-kappaB 鲁棒信息处理的机制

• 批准号: 9884554
• 负责人: Savas Tay
• 金额: $ 35.53万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884554
• 关键词: Affect; Attention; Autoimmune Diseases; Autoimmunity; Back; Bacteria; Biological; Biological Models; Biology; Buffers; CRISPR/Cas technology; Cell Culture Techniques; Cells; Cellular biology; Chronic; Complex; Data; Decision Making; Disease; Double-Stranded RNA; Environment; Feedback; Fibroblasts; Gene Expression; Gene Expression Regulation; Immune; Immune response; Immune signaling; Immunity; Individual; Infection; Inflammation; Knock-out; Ligands; Malignant Neoplasms; Maps; Measurement; Measures; Medical; MicroRNAs; Microfluidic Microchips; Microfluidics; Modeling; Molecular; NF-kappa B; Nature; Noise; Organism; Output; Pathway interactions; Pharmacology; Positioning Attribute; Process; Reporting; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Stimulus; System; TNF gene; Techniques; Testing; Therapeutic; Tissues; Translations; Virus Diseases; Zymosan; cytokine; digital; experience; experimental study; fungus; improved; information processing; insight; knock-down; mathematical methods; mathematical model; network architecture; operation; pathogen; prevent; receptor; response; simulation; single cell analysis

Understanding Mechanisms of Robust Information Processing by NF-κB A major open question in biology is how do cells operate robustly despite ever-present biological noise? Inputs received by cells are unavoidably noisy due to variable translation and secretion of signaling factors, propagation in tissues and stochastic fluctuations in molecular concentrations. Yet, somehow cells are able to accurately process these noisy inputs and create appropriate responses regularly. This proposal aims to answer this fundamental question by studying the effect of noise on gene regulation by the well-known and medically important innate immune signaling pathway NF-B. Attempts at understanding dynamic gene regulation by NF-B and the molecular mechanisms that deal with noise have generally been hampered by significant cell-to-cell variability (requiring single cell analyses), and technical limitations in studying live cells under dynamical signals. Here, we will combine our experience in NF-B signaling, established microfluidic cell culture techniques and mathematical modeling to study this most interesting problem in single cells. Our lab is uniquely positioned to explore and answer this new field, as we have spent the last 10 years constructing and improving the experimental and mathematical methods to study the effect of noise in cellular decision making. Answering this question will have a profound impact on both our basic understanding of cellular decision-making processes, as well as implications in preventing and treating diseases like infection, autoimmunity and cancer.

理解核因子-κB的健壮信息处理机制 生物学中的一个重大悬而未决的问题是，尽管生物噪音无处不在，但细胞是如何稳健运行的？ 由于信号因子的可变翻译和分泌，细胞接收的输入不可避免地存在噪声， 组织中的传播和分子浓度的随机波动。然而，不知何故，细胞能够 以准确处理这些噪声输入，并定期创建适当的响应。这项建议旨在 通过研究噪声对基因调控的影响来回答这个基本问题，由著名的 医学上重要的先天免疫信号通路NF-B试图了解动态基因 核因子-B的调节和处理噪声的分子机制通常受到 细胞间显著的可变性(需要单细胞分析)，以及活体研究中的技术限制 处于动态信号下的细胞。在这里，我们将结合我们在NF-B信令方面的经验， 微流控细胞培养技术和数学模型来研究这一最有趣的问题 单细胞。我们的实验室在探索和回答这一新领域方面具有得天独厚的优势，因为我们花了最后一段时间 10年来建立和完善实验和数学方法来研究 蜂窝决策中的噪音。回答这个问题将对我们两国的基本国情产生深远的影响 对细胞决策过程的理解，以及对预防和治疗的影响 感染、自身免疫和癌症等疾病。