Computational Biology of Vascular Cell Behavior

血管细胞行为的计算生物学

• 批准号: 6780415
• 负责人: CHARLES D. LITTLE
• 金额: $ 36.45万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780415
• 关键词: angiogenesis; aorta; bioassay; biological signal transduction; cell growth regulation; cell morphology; cell proliferation; chick embryo; computational biology; computer simulation; digital imaging; embryo /fetus tissue /cell culture; embryogenesis; enzyme activity; fluorescence microscopy; growth factor receptors; integrins; laboratory mouse; protein tyrosine kinase; quail; time resolved data; vascular endothelial growth factors; vascular endothelium

Vessel formation from mesodermal precursors, vasculogenesis, is regulated by a complex interplay of positive and negative factors acting on endothelial cells. Overlapping morphogenetic events include: i) establishment of the endothelial lineage, ii) positioning and patterning of primordial endothelial cells, iii) formation of lumens, iv) establishment of a primary polygonal network, and v) elaboration of larger vessels. At stages before circulation begins, large caliber vessels, such as the aortae, form when the lumens of neighboring primary tubes coalesce. We use the term vascular fusion to describe the mechanism by which small caliber tubes fuse so as to form large caliber vessels. We previously showed that formation of the aorta is regulated, at least partially, by VEGF signaling and integrin-mediated adhesion. Neutralization of integrin alphavbeta3 activity prevents vascular fusion, while VEGF overstimulation promotes vascular fusion. The hypothesis to be tested is that precise local interactions between VEGF and specific integrins regulate endothelial cell motility and shape changes resulting in the degree of vascular fusion or the absence of vascular fusion. These vasculogenic events take place in ten hours during the second day of quail gestation. The specific aims of this work are: 1) to analyze VEGFR-1 versus VEGFR-2 mediated signaling in primordial endothelial cells, 2) to examine the role integrins alphavbeta3 and alpha5beta1 play in vascular fusion, and 3) to establish computational bioassays with which to quantify individual and collective endothelial cell behaviors. Primordial endothelial cells will be examined using time-lapse microscopy and specific markers in avian embryos. Convincing quantitative data will be produced that describe endothelial velocity, trajectory and persistence time of motility during tube formation, in vivo. The long-term objective is to compile a database for future computer modeling of vasculogenesis. Collectively, this work will contribute to our knowledge of embryonic and adult neovascular processes. Understanding vessel development is of overwhelming clinical importance. Our goal and the goal of other vascular biologists is to explain the mechanisms that promote or inhibit vessel growth. The dynamic embryonic environment provides an ideal opportunity to examine vascular morphogenesis in precise detail.

中胚层前体的血管形成，即血管发生，受到作用于内皮细胞的正负因素的复杂相互作用的调节。 重叠的形态发生事件包括：i) 内皮谱系的建立，ii) 原始内皮细胞的定位和模式化，iii) 管腔的形成，iv) 初级多边形网络的建立，以及 v) 较大血管的形成。 在循环开始之前的阶段，当相邻主管的管腔合并时，会形成大口径血管，例如主动脉。 我们使用术语血管融合来描述小口径管融合以形成大口径血管的机制。 我们之前表明，主动脉的形成至少部分受到 VEGF 信号传导和整合素介导的粘附的调节。 整合素 αvβ3 活性的中和可防止血管融合，而 VEGF 过度刺激可促进血管融合。 待测试的假设是 VEGF 和特定整合素之间精确的局部相互作用调节内皮细胞运动和形状变化，从而导致血管融合的程度或不存在血管融合。 这些血管生成事件发生在鹌鹑妊娠第二天的十小时内。这项工作的具体目的是：1) 分析原始内皮细胞中 VEGFR-1 与 VEGFR-2 介导的信号传导，2) 检查整合素 alphavbeta3 和 alpha5beta1 在血管融合中的作用，3) 建立计算生物测定法，量化个体和集体内皮细胞行为。 将使用延时显微镜和鸟类胚胎中的特定标记来检查原始内皮细胞。将产生令人信服的定量数据，描述体内管形成过程中的内皮运动速度、轨迹和持续时间。 长期目标是为未来血管生成的计算机建模编制数据库。 总的来说，这项工作将有助于我们了解胚胎和成人新生血管过程。了解血管发育具有压倒性的临床重要性。 我们的目标和其他血管生物学家的目标是解释促进或抑制血管生长的机制。 动态胚胎环境提供了精确详细地检查血管形态发生的理想机会。