computational systems analysis of dopamine metabolism计算系统分析多巴胺代谢的.pdf

Computational Systems Analysis of Dopamine Metabolism 1,2,3 2,3 1 Zhen Qi , Gary W. Miller , Eberhard O. Voit * 1 Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Medical School, Atlanta, Georgia, United States of America, 2 Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America, 3 Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia, United States of America Abstract A prominent feature of Parkinson’s disease (PD) is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metab