Collaborative Research: Modeling Stochastic Spatial Effects in Epithelial Mesenchymal Transformation, Signaling, and Cell Migration and Invasion

合作研究：模拟上皮间质转化、信号传导以及细胞迁移和侵袭中的随机空间效应

• 批准号: 1361411
• 负责人: Marek Kimmel
• 金额: $ 70万
• 依托单位: William Marsh Rice University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1361411&HistoricalAwards=false
• 关键词: Collaborative; Research; Modeling; Stochastic; Spatial

It has been discovered that cancerous tumors are capable of enrolling support from "normal" cells of the host organism. Some of these cells are then reverting to normally suppressed behaviors such as mobility and invasion as well as resistance to cell death. In the process, cells also lose ability to organize themselves into sheets and other structures common in normal tissue. This process is known as the epithelial-mesenchymal transformation (EMT). Motivated by this example, the investigators developed an experimental model of one type of EMT and, along with biological experiments, are now able to reproduce some features of EMT in computers, i.e., to model the EMT mathematically. In the current project, the investigators pursue research based on these preliminary results. These experiments and computer models give rise to a better understanding of signaling processes and, in some cases, leads to better predictions of the effect of treatments on behavior of cancer cells, thus helping advance the fight against cancer.In more technical terms, the objective of the proposed research is multidisciplinary and multiscale analysis of the Epithelial Mesenchymal Transformation (EMT). EMT is the process by which epithelial cells reversibly lose baso-apical polarity and cell-cell junctions, acquiring plasticity, mobility, invasivity, stem-cell characteristics, and resistance to apoptosis. This mechanism is important in embryogenesis, as well as in wound healing and in cancer metastasis. The investigators are particularly interested in the role of NF-kB and p53 and their crosstalk in cancer-related (type III) EMT. The goal is to build a mathematical model that will relate signal transduction pathways to changes in cell behavior, focusing on observing and modeling cell motility. An experimental system is developed to measure motility and proliferation using the new Cell Tracker software and Lineage Tracker for quantitation. Gene expression and flow cytometry measurements will be included. Preliminary data show activation of the NFkB pathway increases motility. Results of the project can be used to reduce cellular invasion in epithelial malignancies, or sensitize cancer cells to chemotherapeutic agents. Although the current study has a basic nature, the resulting insights will inform biomedically oriented applications.

已经发现，癌性肿瘤能够从宿主生物体的“正常”细胞获得支持。 然后，这些细胞中的一些恢复到正常受抑制的行为，如迁移和入侵以及对细胞死亡的抵抗。在这个过程中，细胞也失去了将自己组织成正常组织中常见的薄片和其他结构的能力。 这个过程被称为上皮-间充质转化（EMT）。受这个例子的启发，研究人员开发了一种EMT的实验模型，沿着生物实验，现在能够在计算机中再现EMT的一些特征，即，来建立急诊医疗队的数学模型 在目前的项目中，研究人员根据这些初步结果进行研究。 这些实验和计算机模型可以更好地理解信号传导过程，在某些情况下，可以更好地预测治疗对癌细胞行为的影响，从而帮助推进抗癌斗争。在更专业的术语中，拟议研究的目标是对上皮间充质转化（EMT）进行多学科和多尺度分析。 EMT是上皮细胞可逆地失去基底-顶端极性和细胞-细胞连接，获得可塑性、移动性、侵袭性、干细胞特征和抗凋亡的过程。 这种机制在胚胎发生、伤口愈合和癌症转移中很重要。 研究人员对NF-kB和p53的作用及其在癌症相关（III型）EMT中的相互作用特别感兴趣。 目标是建立一个数学模型，将信号转导途径与细胞行为的变化联系起来，重点是观察和建模细胞运动。 开发了一个实验系统，使用新的Cell Tracker软件和Lineage Tracker定量测量运动和增殖。 将包括基因表达和流式细胞术测量。初步数据显示NFkB途径的激活增加运动性。 该项目的结果可用于减少上皮恶性肿瘤的细胞侵袭，或使癌细胞对化疗药物敏感。 虽然目前的研究具有基本性质，但由此产生的见解将为面向生物医学的应用提供信息。