A CELL-BASED MODEL OF TUMOR-INDUCED ANGIOGENESIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肿瘤诱导的血管生成，即响应于来自肿瘤的化学信号而从现有脉管系统形成新血管，是癌症发展和进展的关键步骤。尽管肿瘤诱导的血管生成中涉及的顺序步骤是众所周知的，但生物化学和生物力学机制之间的相互作用（例如，细胞-细胞相互作用、细胞-基质相互作用和细胞内信号传导途径）及其对血管生成的影响在很大程度上尚未解决。本研究的重点是开发一种基于细胞的肿瘤诱导的血管生成模型，该模型结合了基质的演变组成以及细胞与其主要成分细胞外基质相互作用的作用，以便更好地了解如何操纵这些过程以获得治疗效果。生物物理模型的关键特征包括以下：（1）连接发生在多个时间尺度上的过程，（2）在连续模型失败的单个细胞水平上控制过程，以及（3）将ECM的积极作用作为刺激血管生成的细胞因子和趋化因子的来源。我们已经开发了一个数字代码，ANGIO，模拟生物物理模型，肿瘤诱导的血管生成。使用ANGIO，我们将解决以下关键科学问题：（1）在内皮细胞迁移中，趋化性和机械力（如细胞粘附到细胞外基质）的相对重要性是什么，（2）细胞外基质的组成和结构如何影响血管生成过程中毛细血管芽的形成，（3）基质重构如何影响细胞迁移和血管结构，以及（4）不同VEGF亚型和VEGF受体在毛细血管引导和形成中的作用。这些结果最终将为开发治疗癌症和其他血管生成依赖性疾病的新方法提供信息和推动努力。我们请求共享内存超级计算资源运行ANGIO，这是一个串行代码。每次运行将在单个处理器上运行10个CPU小时。对于上面的每个任务，我们将进行大约1000次运行，以探索参数范围并收集统计数据。因此，我们将需要30，000 CPU超级计算小时。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tumor-induced angiogenesis, the formation of new blood vessels from existing vasculature in response to chemical signals from a tumor, is a crucial step in cancer development and progression. Although the sequential steps involved in tumor-induced angiogenesis are well known, the interplay between the biochemical and biomechanical mechanisms (e.g., cell-cell interactions, cell-matrix interactions, and intracellular signaling pathways) and their effects on angiogenesis is largely unresolved. The focus of this research is to develop a cell-based model of tumor-induced angiogenesis that incorporates the evolving composition of the stroma and the role of cellular interactions with its major component, the extracellular matrix, in order to better understand how to manipulate these processes for therapeutic gain. Key features of the biophysical model include the following: (1) linking processes occurring on multiple time scales, (2) controlling processes at the level of the individual cell where continuous models fail, and (3) incorporating the active role of the ECM as a source of cytokines and chemokines that stimulate angiogenesis. We have developed a numerical code,ANGIO, that simulates the biophysical model, of tumor-induced angiogenesis. Using ANGIO, we will address the following key scientific questions: (1) what is the relative importance of chemotaxis and mechanical forces, such as cellular adhesion to the extracellular matrix, in endothelial cell migration, (2) how does the extracellular matrix composition and structure influence capillary sprout formation during angiogenesis, (3) how does matrix restructuring affect cell migration and vascular structure, and (4) what is the role of different VEGF isoforms and VEGF receptors in capillary guidance and formation. The results should ultimately inform and advance efforts to develop new approaches for treating cancer and other angiogenesis-dependent diseases. We request the shared memory supercomputing resources to run ANGIO, which is a serial code. Each run will be on a single processor for 10 CPU hours. For each task above, we will conduct about 1000 runs to explore the parameter ranges and to collect statistics. Hence we will requst 30,000 CPU supercomputing hours.