Spatial Monte Carlo models for VEGF binding on the cell membrane

描述（由申请人提供）：血管内皮生长因子（VEGF）信号传导控制血管发育，并在恶性肿瘤的血管形成中发挥核心作用。VEGF最重要的受体是受体酪氨酸激酶（RTK）家族的一部分。受体二聚化是RTK受体活化的重要步骤。受体在岛中的浓度或聚集代表总膜表面的一小部分是RTK信号传导的另一个特征，据信增加了其效率。 这些现象在信号传导中的作用以及受体聚集的起源和机制尚未得到很好的理解，并且受到密集的实验和理论努力的影响。这个关于VEGF的项目补充了正在进行的工作，重点是其他RTK受体家族，如EGF。 我们建议调查VEGF信号的动力学中的空间结构的作用，并推断VEGF受体在细胞膜中的空间分布及其对配体存在的依赖性，在一个特定的细胞系统。在实验上，我们计划使用先进的成像方法，使个别受体的可视化，并推断其空间分布和流动性，以及流式细胞术，以调查在个别细胞的信号。 基于在相同细胞系统上收集的数据，我们将建立信号传导中涉及的分子过程的空间蒙特-卡罗模型，包括细胞膜中的二维运动。我们将使用这个模型来研究细胞膜的空间特征、受体聚集和信号转导之间的相互作用。 最后，我们试图封装的空间方面的VEGF结合在较低的维度表示的新兴的理解，定义一个现实的，全细胞模型的第一步，在VEGF信号转导，它可以被纳入模型的组织规模的目标。

DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF) signaling controls blood vessel development and plays a central role in the vascularization of malignant tumors. The most important receptors for VEGF are part of the receptor tyrosine kinase (RTK) family. Receptor dimerization is an important step in the activation of RTK receptors. Concentration or clustering of receptors in islands representing a small fraction of the total membrane surface is another feature of RTK signaling, believed to increase its efficiency. The role of these phenomena in signaling and the origin and mechanism of receptor clustering are not well understood and are subject to intense experimental and theoretical efforts. This project on VEGF complements ongoing work focused on other RTK receptor families such as EGF. We propose to investigate the role of spatial structure in the kinetics of VEGF signaling and infer the spatial distribution of VEGF receptors in the cell membrane and its dependence on the presence of ligand, in a specific cell system. Experimentally we plan to use advanced imaging methods which allow the visualization of individual receptors and infer their spatial distribution and mobility, as well as flow cytometry to investigate signaling in individual cells. Based on data collected on the same cellular system, we will build a spatial Monte-Carlo model of the molecular processes involved in signaling, including two-dimensional movement in the cell membrane. We will use this model to investigate the interplay between spatial features of the cell membrane, receptor clustering, and signal transduction. Finally, we seek to encapsulate the emerging understanding of spatial aspects of VEGF binding in lower dimensional representations, with the goal of defining a realistic, whole-cell model of the first step in VEGF signaling, which can be incorporated in models on the scale of tissues.