Collaborative Research: Multicellular Communication in Gradient Sensing

合作研究：梯度感知中的多细胞通信

• 批准号: 1410978
• 负责人: Ilya Nemenman
• 金额: $ 20万
• 依托单位: Emory University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1410978&HistoricalAwards=false
• 关键词: Collaborative; Research; Multicellular; Communication; Gradient

Epidermal growth factor gradient sensing by epithelial cells is a crucial process in development and many disease processes such as cancer metastasis. Understanding the basic principles of this sensing would enable us to intervene in disease processes that involve directional cell motion by pharmacologically targeting the communication rather than the within-cell regulation, and it can stimulate a novel direction for therapeutics. Through a combination of novel experimental and theoretical approaches, this project will characterize advantages and limitations of multicellular gradient sensing in breast epithelial tissue in a mouse model. It will explore the fundamental physical limits on collective gradient sensing and will establish to which extent the size of multicellular ensembles aids their sensory precision. The project will also support synergistic curriculum development efforts on the interface of physics and biology at three research universities, on levels from introductory undergraduate to advanced graduate. It will provide research and broader career training opportunities for undergraduate and graduate students and postdocs, including minority students. The PIs will engage elementary school students in science projects and they will reach out to the general public disseminating their research findings at the Atlanta Science Festival.Cells in multicellular organisms rarely act alone in responding to external signals, but little is known about behaviors that emerge from their multicellular, collective communication and action. In particular it is unknown if multicellular ensembles can collectively sense chemical gradients in ways that take advantage of such ensembles spanning substantial ranges of the chemo-attractant concentration. The PIs' experiments with multicellular ensembles of breast epithelial cells exposed to gradients of epidermal growth factor suggest that these cells can sense gradients collectively and that collectively cells respond to gradients that are far smaller than those sensed by individual cells. This multicellular information processing is fundamentally distinct from, and not simply reducible to, sensory processes in isolated cells. The PIs will establish theoretically and verify experimentally the fundamental physical limits on the precision of gradient sensing by multicellular ensembles. These limits containing contributions from the extrinsic ligand stochasticity and from the intrinsic noise in communicating the measurements made by distant cells in a multicellular group to individual cells within the group will be characterized. The PIs will develop computational methods to analyze precision of biological information processing in collective, nonlinear phenomena, such as epithelial tissue rearrangement, which will be applicable broadly in other biophysical contexts.

上皮细胞的表皮生长因子梯度传感是发育中的关键过程和许多疾病过程，例如癌症转移。了解这种感应的基本原理将使我们能够干预涉及药理靶向通信而不是细胞内调节的疾病过程，并且可以刺激治疗方法的新方向。通过新型实验和理论方法的结合，该项目将表征小鼠模型中乳腺上皮组织中多细胞梯度感应的优势和局限性。它将探索集体梯度感应的基本物理限制，并确定多细胞合奏的大小有助于他们的感觉精度。该项目还将支持三所研究大学物理和生物学界面的协同课程开发工作，从入门本科到高级毕业生的水平。它将为包括少数族裔学生在内的本科和研究生和博士学位提供研究和更广泛的职业培训机会。 PI将吸引小学学生参与科学项目，他们将与公众接触，在亚特兰大科学节上传播他们的研究结果。多细胞生物的细胞很少单独采取响应外部信号，但对从其多细胞，集体沟通和行动中脱颖而出的行为知之甚少。特别是尚不清楚多细胞集合是否能以利用这种合奏的方式集体地感知化学梯度，从而跨越了化学吸引浓度的大量范围。暴露于表皮生长因子梯度的乳腺上皮细胞的多细胞集合的PIS实验表明，这些细胞可以集体触发梯度，并且集体对细胞的响应响应于远小于单个细胞所感知的梯度。这种多细胞信息处理从根本上是与孤立细胞中的感官过程相区别的，而不是简单地降低的。 PI将在理论上并在实验上验证多细胞合奏的梯度感测精度的基本物理极限。这些限制包含来自外部配体随机性的贡献以及从多细胞组中远处细胞与该组中单个细胞进行的测量的内在噪声的贡献。 PI将开发计算方法，以分析集体非线性现象中的生物信息处理的精度，例如上皮组织重排，这些重排将广泛适用于其他生物物理环境。