Adhesive dynamics simulation of neutrophil arrest with deterministic activation
Adhesive dynamics simulation of neutrophil arrest with deterministic activation
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DOI：
10.1529/biophysj.105.070706
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发表时间：
2006-08-15
影响因子：
3.4
通讯作者：
Hammer, Daniel A.
中科院分区：
文献类型：
--
作者：
Krasik, Ellen F.;Yee, Ka Lai;Hammer, Daniel A.
从滚动到牢固粘附的转变是中性粒细胞激活的关键要素，并且对于炎症反应至关重要。尽管已知滚动和牢固粘附的分子介质分别是选择素和β(2)-整联蛋白，但这些配体促进中性粒细胞停滞的精确动态机制仍然未知。最近，研究表明，E-选择素的连接可以通过 MAP-激酶级联刺激中性粒细胞的牢固粘附。为了研究中性粒细胞停滞发生的可能机制，我们通过结合计算生物学的两种方法创建了一个集成模型：基于力学的白细胞粘附建模（粘附动力学）和信号转导通路建模。在粘附动力学中，我们的团队已经证明了一种可以准确地重建滚动动力学的计算方法，我们包括一个通用的、可调节的整合素激活模块，该模块将选择蛋白的参与与整合素和活性联系起来。该模型使我们能够将激活函数的属性与滚动动力学以及逮捕前滚动的时间和距离联系起来。这个集成模型使我们能够了解细胞内信号传导活动如何设定中性粒细胞激活、粘附和血细胞渗出的时间尺度。
The transition from rolling to firm adhesion is a key element of neutrophil activation and essential to the in. ammatory response. Although the molecular mediators of rolling and firm adhesion are known to be selectins and beta(2)- integrins, respectively, the precise dynamic mechanism by which these ligands facilitate neutrophil arrest remains unknown. Recently, it has been shown that ligation of E-selectin can stimulate the firm adhesion of neutrophils via a MAP-kinase cascade. To study the possible mechanism by which neutrophil arrest could occur, we created an integrated model by combining two methodologies from computational biology: a mechanics-based modeling of leukocyte adhesion (adhesive dynamics) and signal transduction pathway modeling. Within adhesive dynamics, a computational method our group has shown to accurately recreate rolling dynamics, we include a generic, tunable integrin activation module that links selectin engagement to integrin and activity. This model allows us to relate properties of the activation function to the dynamics of rolling and the time and distance rolled before arrest. This integrated model allows us to understand how intracellular signaling activity can set the timescale of neutrophil activation, adhesion, and diapedesis.