Collaborative Research: Multicellular Communication in Gradient Sensing

上皮细胞对表皮生长因子梯度的感知是发育和许多疾病过程（如癌症转移）的重要过程。了解这种感知的基本原理将使我们能够通过药物靶向通讯而不是细胞内调节来干预涉及定向细胞运动的疾病过程，并且可以刺激治疗的新方向。通过新颖的实验和理论方法的结合，本项目将在小鼠模型中描述乳腺上皮组织中多细胞梯度传感的优点和局限性。它将探索集体梯度传感的基本物理限制，并将确定多细胞集合的大小在多大程度上有助于它们的传感精度。该项目还将支持三所研究型大学从本科入门到高级研究生的物理和生物交叉学科的协同课程开发工作。它将为本科生、研究生和博士后（包括少数民族学生）提供研究和更广泛的职业培训机会。pi将让小学生参与科学项目，他们将在亚特兰大科学节上向公众传播他们的研究成果。多细胞生物中的细胞很少单独响应外部信号，但对它们的多细胞集体交流和行动所产生的行为知之甚少。特别是，目前尚不清楚多细胞集合是否可以利用这些跨越化学引诱剂浓度大范围的集合来集体感知化学梯度。pi对暴露于表皮生长因子梯度下的乳腺上皮细胞的多细胞群进行的实验表明，这些细胞可以集体感知梯度，并且集体细胞对远小于单个细胞感知梯度的梯度作出反应。这种多细胞信息处理从根本上不同于孤立细胞中的感觉过程，而不是简单地归结为感觉过程。pi将从理论上和实验上验证多细胞集成梯度传感精度的基本物理限制。这些限制包括来自外部配体随机性的贡献，以及来自多细胞群体中远端细胞与群体内单个细胞通信测量时的固有噪声的贡献，将被表征。pi将开发计算方法来分析集体非线性现象（如上皮组织重排）中生物信息处理的精度，这将广泛适用于其他生物物理环境。

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.