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

职业：建立集体细胞传感理论并应用于形态发生、趋化性和转移

• 批准号: 2118561
• 负责人: Andrew Mugler
• 金额: $ 69.24万
• 依托单位: University of Pittsburgh
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2118561&HistoricalAwards=false
• 关键词: CAREER; Building; Theory; Collective; Cellular

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.

过去40年的理论和实验工作已经证实，单细胞的感觉精度接近物理可能的极限。然而，过去十年的实验表明，当细胞相互作用时，感觉的精确度会进一步提高。这些实验很吸引人，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一个全面的集体细胞感知理论来解决这个问题。该项目集中在三个细胞生物学的例子-果蝇的形态发生，大肠杆菌的趋化性。大肠杆菌，以及乳腺癌和黑色素瘤细胞的转移，其中实验表明细胞间通讯增强了传感，但增强的机制知之甚少。在每种情况下，将根据系统的已知特征开发理论框架，并使用实验数据验证该框架。研究、教育和推广活动的设计是以一种密切相关的方式进行的，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传播。该研究将通过一个基于探究的教学模块和PI研究生和本科生课程中的跨学科单元融入教育。设计和试点与研究生，部门外展协调员，和当地高中教师合作，活动将在校园内交付，在印第安纳州中学服务代表性不足的学生，并在全州和全国教育会议，从而达到成千上万的初中和高中学生，特别是代表性不足的学生。特别侧重于开发和评估微生物学，显微镜，统计学和数字感的知识。在发育过程中，感觉的精确性至关重要，因为细胞通过感知被称为形态发生素的分子的浓度来决定它们的命运。最近的实验表明，短距离细胞间通讯可能有助于提高形态发生蛋白形成的精确性和细胞命运边界的建立，但其机制仍不清楚。PI将开发一种具有短距离通信的浓度传感理论，使用之前在果蝇和斑马鱼胚胎中的实验进行验证，并为未来的形态发生实验做出预测。此外，PI将建立一个远程通信的理论，并将其应用于细菌的趋化性。细菌通过感知引诱物浓度的梯度而向有利的环境移动，这一过程被称为趋化性。最近的实验表明，趋化性增强的远距离细胞间通讯，但增强机制是未知的。为了解决这个问题，PI将开发一种具有远程通信的梯度感应和趋化性理论，并使用先前在E.大肠杆菌，并为未来的趋化性实验，包括那些合作实验室的预测。PI还将建立一个自我沟通的理论，并将其应用于癌症转移。许多癌细胞通过感知淋巴流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（释放一种分子，他们也检测），但这种机制的细节仍然知之甚少，PI将开发一种通过自我通信的流量传感理论，使用以前对乳腺癌和黑色素瘤细胞的实验来验证它，该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的评估来支持。影响审查标准。

项目成果

Precision of Protein Thermometry

• DOI: 10.1103/physrevlett.127.098102
• 发表时间: 2021-08-26
• 期刊: PHYSICAL REVIEW LETTERS
• 影响因子: 8.6
• 作者: Vennettilli, Michael;Saha, Soutick;Mugler, Andrew
• 通讯作者: Mugler, Andrew

Cells function as a ternary logic gate to decide migration direction under integrated chemical and fluidic cues.

• DOI: 10.1039/d2lc00807f
• 发表时间: 2023-02-14
• 期刊: Lab on a chip
• 影响因子: 6.1

Multicellular sensing at a feedback-induced critical point

反馈诱导临界点的多细胞传感

• DOI: 10.1103/physreve.102.052411
• 发表时间: 2020
• 期刊: Physical Review E
• 影响因子: 2.4
• 作者: Vennettilli, Michael;Erez, Amir;Mugler, Andrew
• 通讯作者: Mugler, Andrew

Deduction of signaling mechanisms from cellular responses to multiple cues.

• DOI: 10.1038/s41540-022-00262-5
• 发表时间: 2022-11-30
• 期刊: NPJ systems biology and applications
• 影响因子: 4

Signal processing capacity of the cellular sensory machinery regulates the accuracy of chemotaxis under complex cues.

细胞感觉机制的信号处理能力调节复杂线索下趋化性的准确性。

• DOI: 10.1016/j.isci.2021.103242
• 发表时间: 2021-11-19
• 期刊: iScience
• 影响因子: 5.8
• 作者: Moon HR;Saha S;Mugler A;Han B
• 通讯作者: Han B