3-D modelling of cell signalling and motility of tumour cells, epithelial tissues and zebrafish morphogenesis.

化学和机械的细胞相互作用贯穿于生物体的整个生命周期，并推动受精卵向成熟成人的转变。理解这种复杂转换的有效方法是通过开发和使用数学模型和计算机模拟这些相互作用。我建议使用基于3-D个体细胞的模型（ICBM）来研究使用三种不同模型系统的一些基本相互作用。每项研究都将回答与正在研究的特定模型系统相关的问题，但综合起来，这项研究将推进我们对细胞信号传导、细胞分化和细胞粘附在发育过程中如何共同作用以形成成熟结构的认识。此外，这种见解扩大了模型的适用性，以更好地理解其他生物系统。***(1)后侧线（pLL）是鱼类发育早期形成的一个感觉系统（用于检测水流）。我将使用洲际弹道导弹来了解pLL原基的极化是如何在pLL发展的早期阶段建立的，并且通过建模关键信号（即Wnt/FGF），我将确定小信号分子（例如趋化因子SDF1a）如何驱动集体向尾部迁移。我还将模拟导致神经肥大（鱼的一种感觉器官）分化和建立的化学相互作用（例如，Wnt， FGF, Notch），这项工作将有助于阐明潜在的机制，这在其他脊椎动物中是共享的。***(2)乳腺肿瘤细胞利用EGF/CSF-1旁分泌信号系统向免疫系统细胞巨噬细胞发出信号，诱导其打开通道进入血管。我将使用我的ICBM来建模并理解这种信号是如何运作的以及它是如何增强肿瘤细胞侵袭的。该模型和预测将使用体外和体内实验的数据进行测试。我的研究结果将对其他旁分泌信号系统，如巨噬细胞和结缔组织细胞（如成纤维细胞）之间的伤口愈合产生影响。***(3)“EMT”是一种过程，在该过程中，在排列表面的组织中发现的非运动细胞，如皮肤（即上皮细胞）经历多重分子变化，失去与其他细胞的附着，并获得运动间充质细胞特征。emt在发育过程中的细胞分化中起着至关重要的作用，也参与组织修复，产生间充质细胞如成纤维细胞。我将使用我的ICBM来模拟和探索在上皮细胞层中启动ETM的充分和必要的粘附和信号分子表达的变化。从细胞和发育的角度以及从疾病预防的角度来看，这些机制都是重要的

Chemical and mechanical cell interactions operate throughout the lifespan of an organism and drive the transformation of a fertilized egg to a mature adult. An effective approach to understanding this complex transformation is through the development and use of mathematical models and computer simulations of these interactions. I propose to use a 3-D individual cell based model (ICBM) to study some of these basic interactions using three different model systems. Each study will answer questions related to the particular model system being investigated, but taken together, the research will advance our knowledge of how cell signaling, cell differentiation and cell adhesion work together during developmental processes to form mature structures. Moreover, such insights expand the applicability of the model to better understand other biological systems.***(1) The posterior lateral line (pLL) is a sensory system (for detecting water flow) formed early in fish development. I will use the ICBM to understand how polarization of the pLL primordium is set up in early stages of pLL development and, by modeling key signals (i.e. Wnt/FGF), I will determine how small signaling molecules (e.g. the chemokine SDF1a) drive collective migration toward the tail. I will also model the chemical interactions (e.g., Wnt, FGF, Notch) that lead to differentiation and establishment of the neuromast, a sensory organ of the fish, work that will help elucidate the underlying mechanism, which is shared among other vertebrates.***(2) Mammary tumor cells use an EGF/CSF-1 paracrine signaling system to signal to immune system cells called macrophages and coax them to open up passages into blood vessels. I will use my ICBM to model and to understand how this signaling operates and how it enhances tumor cell invasion. The model and predictions will be tested using data from both in vitro and in vivo experiments. My results will have implications for other paracrine signaling systems, such as between macrophages and connective tissue cells (e.g. fibroblasts) in wound healing.***(3) ‘EMT' is a process where a non-motile cell found in the tissues that line surfaces, such as the skin (i.e. an epithelial cell) undergoes multiple molecular changes, loses attachment to other cells and acquires a motile mesenchymal cell characteristic. EMTs play crucial roles in cell differentiation during development and are also involved in tissue repair, producing mesenchymal cells such as fibroblasts. I will use my ICBM to model and explore the changes in expression of adhesion and signaling molecules that are sufficient and necessary to initiate ETM in an epithelial cell layer. These mechanisms are important from a cell and developmental perspective, as well as from a disease prevention angle.**