Spatial Monte Carlo models for VEGF binding on the cell membrane

描述(申请人提供)：血管内皮生长因子(VEGF)信号控制血管发育，并在恶性肿瘤的血管形成中发挥核心作用。最重要的血管内皮生长因子受体是受体酪氨酸激酶(RTK)家族的一部分。受体二聚化是RTK受体激活的重要步骤。RTK信号的另一个特点是受体集中或聚集在岛屿上，代表整个膜表面的一小部分，被认为可以提高其效率。 这些现象在信号传递中的作用以及受体聚集的起源和机制还不是很清楚，还需要进行大量的实验和理论研究。这项关于血管内皮生长因子的项目补充了正在进行的专注于其他RTK受体家族的工作，如EGF。 我们建议研究空间结构在血管内皮生长因子信号动力学中的作用，并推断特定细胞系统中血管内皮生长因子受体在细胞膜上的空间分布及其对配体存在的依赖性。在实验上，我们计划使用先进的成像方法，使单个受体可视化，并推断它们的空间分布和迁移率，以及使用流式细胞术来研究单个细胞中的信号。 基于在同一细胞系统上收集的数据，我们将建立一个涉及信号传递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，我们试图将新兴的对血管内皮生长因子结合的空间方面的理解封装在较低维度的表示中，目的是定义一个现实的、完整的血管内皮生长因子信号第一步的全细胞模型，该模型可以并入组织规模的模型中。

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.