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Identifying Key Pathways and Components in Chemokine-Triggered T Lymphocyte Arrest Dynamics Using a Multi-Parametric Global Sensitivity Analysis.
Cellular and Molecular Bioengineering ( IF 2.8 ) Pub Date : 2019-05-29 , DOI: 10.1007/s12195-019-00575-2 Dooyoung Lee 1, 2 , Michael T Beste 3, 4 , Nicholas R Anderson 3 , Gary A Koretzky 5, 6, 7, 8 , Daniel A Hammer 1, 3
中文翻译:
使用多参数全局敏感性分析识别趋化因子触发的 T 淋巴细胞阻滞动力学中的关键途径和成分。
更新日期:2019-05-29
Cellular and Molecular Bioengineering ( IF 2.8 ) Pub Date : 2019-05-29 , DOI: 10.1007/s12195-019-00575-2 Dooyoung Lee 1, 2 , Michael T Beste 3, 4 , Nicholas R Anderson 3 , Gary A Koretzky 5, 6, 7, 8 , Daniel A Hammer 1, 3
Affiliation
Introduction
The arrest of rolling T lymphocytes at specific locations is crucial to proper immune response function. We previously developed a model of chemokine-driven integrin activation, termed integrative signaling adhesive dynamics (ISAD). In addition, we have shown that loss of diacylglycerol kinase (DGK) leads to a gain of function regarding adhesion under shear flow. We undertook this study to understand the sensitivity of adhesion to perturbations in other signaling molecules.Methods
We adapted multi-parametric sensitivity analysis (MPSA) for use in our ISAD model to identify important parameters, including initial protein concentrations and kinetic rate constants, for T lymphocyte arrest. We also compared MPSA results to those obtained from a single parametric sensitivity analysis.Results
In addition to the previously shown importance of DGK in lymphocyte arrest, PIP2 cleavage and Rap1 activation are crucial in determining T cell arrest dynamics, which agree with previous experimental findings. The l-selectin density on the T lymphocyte surface also plays a large role in determining the distance rolled before arrest. Both the MPSA and single-parametric method returned similar results regarding the most sensitive kinetic rate constants.Conclusion
We show here that the regulation of the amount of second messengers are, in general, more critical for determining T lymphocyte arrest over the initial signaling proteins, highlighting the importance of amplification of signaling in cell adhesion responses. Overall, this work provides a mechanistic insight of the contribution of key pathways and components, thus may help to identify potential therapeutic targets for drug development against immune disorders.中文翻译:
使用多参数全局敏感性分析识别趋化因子触发的 T 淋巴细胞阻滞动力学中的关键途径和成分。