A CELL-BASED MODEL OF TUMOR-INDUCED ANGIOGENESIS

基于细胞的肿瘤诱导血管生成模型

• 批准号: 7601386
• 负责人: TRACHETTE L. JACKSON
• 金额: $ 0.03万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601386
• 关键词: Address; Affect; Biochemical; Biomechanics; Blood Vessels; Blood capillaries; Cell Adhesion; Cell Communication; Cells; Chemicals; Chemotaxis; Code; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Endothelial Cells; Extracellular Matrix; Funding; Grant; Hour; Individual; Institution; Link; Malignant Neoplasms; Mechanics; Modeling; Process; Protein Isoforms; Range; Relative (related person); Research; Research Personnel; Resources; Role; Running; Signal Pathway; Signal Transduction; Simulate; Source; Structure; Supercomputing; Therapeutic; Time; United States National Institutes of Health; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; angiogenesis; base; capillary; cell motility; chemokine; cytokine; novel strategies; response; shared memory; statistics; tumor

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肿瘤诱导的血管生成是肿瘤发生和发展过程中的关键一步，肿瘤诱导的血管生成是对肿瘤化学信号作出反应的新血管的形成。虽然肿瘤诱导血管生成的一系列步骤是众所周知的，但生化和生物力学机制(如细胞-细胞相互作用、细胞-基质相互作用和细胞内信号通路)及其对血管生成的影响之间的相互作用在很大程度上还没有解决。这项研究的重点是建立一个基于细胞的肿瘤诱导血管生成模型，该模型结合了间质的不断演变的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收益。生物物理模型的主要特征包括：(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)结合细胞外基质作为刺激血管生成的细胞因子和趋化因子的来源的积极作用。我们开发了一个名为Angio的数值代码，它模拟了肿瘤诱导的血管生成的生物物理模型。利用Angio，我们将解决以下关键的科学问题：(1)趋化性和机械力(如细胞与细胞外基质的黏附)在内皮细胞迁移中的相对重要性；(2)在血管生成过程中，细胞外基质的组成和结构如何影响毛细血管的萌芽形成；(3)基质重组如何影响细胞迁移和血管结构；以及(4)不同的VEGF异构体和VEGF受体在毛细血管引导和形成中的作用。这些结果最终应该会为开发治疗癌症和其他血管生成依赖型疾病的新方法提供信息并推动努力。我们请求共享内存的超级计算资源来运行Angio，这是一个串行码。每次运行将在单个处理器上运行10个CPU小时。对于上述每项任务，我们将进行约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个CPU超级计算小时。