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.

过去四十年来的理论和实验工作已经确定，单细胞的感觉精度接近了物理上可能的限制。但是，在过去十年中的实验表明，当细胞相互作用时，感觉精度甚至进一步提高。这些实验令人着迷，并提出了有关感官合作，信息共享和集体行为的许多基本问题。该项目将通过发展集体蜂窝传感的全面理论来解决这个问题。该项目的重点是细胞生物学的三个例子 - 果蝇中的形态发生，大肠杆菌中的趋化性以及乳腺癌和黑色素瘤细胞的转移，在其中实验表明细胞 - 细胞通信增强了感应，但增强的机制知之甚少。在每种情况下，都会根据系统的已知功能开发一个理论框架，并将使用实验数据验证该框架。研究，教育和外展活动的设计以强烈的互连方式设计，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分发。这项研究将通过基于询问的教学模块和PI毕业生课程中的基于询问的教学模块和跨学科单位纳入教育。该活动设计和驾驶，与研究生，部门外展协调员以及当地的高中老师合作，​​将在校园内，印第安纳中学，为代表性不足的学生提供服务，并在州范围内和国民教育会议上进行，从而接触成千上万的中学和高中生，特别是代表不足的学生。特别的重点放在开发和评估微生物学，显微镜，统计和数字意义上。感觉精度在发育过程中至关重要，因为细胞通过传感分子的传感浓度来确定其命运。最近的实验表明，短距离细胞 - 细胞通信可能有助于提高形态形成的精度和建立细胞命运边界，但仍不清楚这些机制。 PI将通过短距离通信发展浓度感测理论，并使用果蝇和斑马鱼胚胎中的先前实验对其进行验证，并为未来的形态发生实验做出预测。此外，PI将建立长期通信的理论，并将其应用于细菌趋化性。细菌通过在吸引人浓度中传感梯度，这一过程称为趋化性。最近的实验表明趋化性通过远程细胞通信增强，但是增强机制尚不清楚。为了解决这个问题，PI将通过长期通信发展梯度感测和趋化性的理论，并使用以前的大肠杆菌细菌上的实验对其进行验证，并为未来的趋化性实验做出预测，包括合作实验室的实验。 PI还将建立自我交流的理论，并将其应用于癌症转移。许多癌细胞通过传感淋巴流传播到人体的其他部位或转移。最近的实验表明，这些细胞通过自我通信（释放了它们也检测到的分子）感知流动，但是该机制的细节仍然很少了解，PI将通过自我交流来发展流动感知的理论，使用自我传感对其进行验证，并使用先前的乳腺癌细胞和黑色素瘤的实验来对其进行验证，并通过对未来的癌症进行宣传。使用基金会的智力优点和更广泛的影响评估标准进行评估。

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

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

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

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.

• 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