Molecular microdosimetry for electric fields

我们建议用分子微剂量学的方法来研究多细胞结构中由于弱电场和强电场引起的生物效应。一种新的模拟方法将用于预测物理量：等电势(电场)、跨膜电压、电流密度和功率耗散密度(SAR)。然后，预测的物理量将与三类生物物理机制(1)电压门控通道，(2)电穿孔和(3)局部加热引起的生化过程的改变)一起用于预测场诱导的分子变化、分子剂量(每细胞的变化)和暴露阈值。如前期工作所证明的，单一的模拟/模型可以同时描述弱场和强场生物电行为。对于弱场和强场，多细胞结构中分子(化学)变化最大的位置将被估计。目标。我们将：(1)进一步发展新的多细胞结构生物电学模拟方法，(2)发展分子微剂量学方法，(3)估计多细胞结构的分子剂量，以及(4)通过定量比较分子剂量与其他来源引起的分子变化来估计各种多细胞结构在弱场和强场下的暴露阈值。意义重大。弱场：了解基于分子变化的多细胞结构阈值是评估50-60赫兹、射频和微波频率下可能的环境场效应的中心问题。强场：体内基于电穿孔的基因治疗、局部抗癌药物输送和电损伤与弱场有一个共同的特征：特定的组织区域预计会优先受累。以前的工作。我们使用生物物理机制模型、分子变化估计和信噪比来估计分离细胞和多细胞结构的弱场阈值，并利用电穿孔的生物物理机制来估计强场下的分子传输和摄取。方法：研究方法。我们将使用已建立的生物物理机制模型和分子变化信噪比方法。新的模拟方法将在单CPU微处理器和(对于计算复杂性更高的问题)Beowulf计算机集群上运行。

We propose investigation of molecular microdosimetry for biological effects due to weak and strong electric fields in multicellular structures. A new simulation method will be used to predict physical quantities: equipotentials (electric fields), transmembrane voltages, current densities and power dissipation density (SAR). The predicted physical quantities will then be used with three classes of biophysical mechanism (1) voltage-gated channels, (2) electroporation and (3) alteration of biochemical processes by local heating) to predict field- induced molecular change, molecular dose (change per cell), and exposure thresholds. As demonstrated in preliminary work, a single simulation/model can describe both weak and strong field bioelectric behavior. The sites of maximum molecular (chemical) change within multicellular structures will be estimated for weak and strong fields. Aims. We will: (1) Further develop the new bioelectric simulation method for multicellular structures, (2) Develop a molecular microdosimetry approach, (3) Estimate molecular dose for multicellular structures, and (4) Estimate exposure thresholds for various multicellular structures for weak and strong fields by quantitatively comparing molecular dose to molecular change due to other sources. Significance. Weak fields: Understanding molecular change-based thresholds for multicellular structures is a central problem in assessing possible environmental field effects at 50 - 60 Hz, RF and microwave frequencies. Strong fields: In vivo electroporation-based gene therapy, localized anticancer drug delivery, and electrical injury share a common feature with weak fields: Particular tissue regions are expected to be preferentially involved. Previous Work. We have used biophysical mechanism models, molecular change estimates and signal-to-noise ratios to estimate weak field thresholds for isolated cells and multicellular structures, and the biophysical mechanism of electroporation to estimate molecular transport and uptake for strong fields. Methods. We will use established biophysical mechanism models and molecular change signal-to-noise ratio methods. The new simulation method will be run on single CPU microprocessors and (for problems with greater computational complexity) a Beowulf computer cluster.