CAREER: Building a Theory of Collective Cellular Sensing with Applications to Morphogenesis, Chemotaxis, and Metastasis

过去四十年的理论和实验工作已经确定，单个细胞的感觉精度接近物理上可能的极限。然而，过去十年的实验表明，当细胞相互作用时，感觉精度甚至会进一步提高。这些实验令人着迷，并提出了许多关于感官合作、信息共享和集体行为的基本问题。这个项目将通过发展集体细胞传感的综合理论来解决这个问题。该项目聚焦于细胞生物学中的三个例子——果蝇的形态发生、大肠杆菌的趋化性以及乳腺癌和黑色素瘤细胞的转移。实验表明，细胞间的交流增强了感知，但增强的机制尚不清楚。在每种情况下，将根据系统的已知特征开发一个理论框架，并使用实验数据验证该框架。研究、教育和推广活动以紧密联系的方式设计，以增加工作的更广泛影响。研究生和本科生将直接进行研究，并通过出版物和会议进行传播。该研究将通过探究式教学模块和PI的研究生和本科课程中的跨学科单元整合到教育中。与研究生、部门外联协调员和一名当地高中教师合作设计和试点的活动将在校园、印第安纳州一所为代表性不足的学生服务的中学、以及全州和全国教育会议上进行，从而惠及数千名初中生和高中生，特别是代表性不足的学生。特别侧重于发展和评估微生物学，显微镜学，统计学和数字感的知识。感觉精度在发育过程中至关重要，因为细胞通过感知被称为形态原的分子的浓度来决定它们的命运。最近的实验表明，近距离细胞间通信可能有助于提高形态因子谱形成的精度和细胞命运边界的建立，但其机制尚不清楚。PI将开发一种具有短距离通信的浓度传感理论，使用先前在果蝇和斑马鱼胚胎上的实验来验证它，并为未来的形态发生实验做出预测。此外，PI将建立远程通信理论并将其应用于细菌趋化性。细菌通过感应引诱剂浓度的梯度向有利环境移动，这一过程被称为趋化性。最近的实验表明，趋化性通过远距离细胞间的交流而增强，但其增强机制尚不清楚。为了解决这个问题，PI将开发一种具有远程通信的梯度传感和趋化性理论，用以前在大肠杆菌上的实验来验证它，并对未来的趋化性实验做出预测，包括合作实验室的实验。PI还将建立自我沟通理论，并将其应用于癌症转移。许多癌细胞通过感知淋巴流动而扩散到身体的其他部位或转移。最近的实验表明，这些细胞通过自我交流来感知流量（释放一种它们也能检测到的分子），但这种机制的细节仍然知之甚少，PI将发展一种通过自我交流来感知流量的理论，用以前在乳腺癌和黑色素瘤细胞上的实验来验证它，并为未来的癌症生物学实验做出预测。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Theoretical and experimental work from the past forty years has established that the sensory precision of single cells approaches the limits of what is physically possible. However, experiments within the past ten years suggest that sensory precision is enhanced even further when cells interact. These experiments are fascinating and raise many fundamental questions about sensory cooperation, information sharing, and collective behavior. This project will address this problem by developing a comprehensive theory of collective cellular sensing. The project focuses on three examples from cell biology - morphogenesis in Drosophila, chemotaxis in E. coli, and metastasis of breast cancer and melanoma cells, where experiments suggest that cell-cell communication enhances sensing, but the mechanism of enhancement is poorly understood. In each case, a theoretical framework will be developed based on known features of the system and the framework will be validated using experimental data. The research, educational, and outreach activities are designed in a strongly interconnected manner to increase the broader impact of the work. Graduate and undergraduate students will directly perform the research and disseminate it through publications and conferences. The research will be integrated into education via an inquiry-based teaching module and cross- disciplinary units in the PI's graduate and undergraduate courses. Designed and piloted in collaboration with graduate students, the departmental outreach coordinator, and a local high school teacher, the activity will be delivered on campus, at an Indiana middle school serving underrepresented students, and at a state-wide and a national education conference, thereby reaching thousands of middle and high school students, particularly underrepresented students. Special focus is placed on developing and assessing knowledge of microbiology, microscopy, statistics, and number sense. Sensory precision is crucial during development because cells determine their fates by sensing concentrations of molecules called morphogens. Recent experiments suggest that short-range cell-cell communication may help increase the precision of morphogen profile formation and the establishment of cell fate boundaries, but the mechanisms are still unclear. The PI will develop a theory of concentration sensing with short- range communication, validate it using previous experiments in Drosophila and zebrafish embryos, and make predictions for future morphogenesis experiments. In addition the PI will build a theory of long-range communication and apply it to bacterial chemotaxis. Bacteria move toward favorable environments by sensing gradients in attractant concentrations, a process called chemotaxis. Recent experiments suggest that chemotaxis is enhanced by long-range cell-cell communication, but the enhancement mechanism is unknown. To address this question the PI will develop a theory of gradient sensing and chemotaxis with long-range communication, validate it using previous experiments on E. coli bacteria, and make predictions for future chemotaxis experiments, including those of a collaborating lab. The PI will also build a theory of self-communication and apply it to cancer metastasis. Many cancer cells spread to other parts of the body, or metastasize, by sensing lymphatic flow. Recent experiments suggest that these cells sense flow by self-communication (releasing a molecule that they also detect), but the details of this mechanism are still poorly understood and the PI will develop a theory of flow sensing via self-communication, validate it using previous experiments on breast cancer and melanoma cells, and make predictions for future cancer biology experiments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.