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研究生(外文):Chao-Min Wang
論文名稱(外文):Reconstruction of Dopaminergic neurons Metabolic Network with Application to Parkinson's Disease
指導教授(外文):Feng-sheng Wang
口試委員(外文):Ann-Ping TsouChi-Ying F. Huang
外文關鍵詞:OptimizationBrain metabolic networkNeurodegenerative Disease
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人類的大腦常伴隨著大量的能量消耗,當能量的供需平衡發生異常時,勢必會造成神經系統地損害,也使其原本所負責的功能喪失,逐漸演變成神經退化性疾病(Neurodegenerative Disease) 。然而研究神經退化性疾病在臨床上需耗費長久的時間,故希望藉由代謝網路模型的建立來模擬出其代謝網絡的通量分布。
本研究利用各個生物資訊庫所提供的資料,建造出屬於人類大腦的多巴胺神經元細胞代謝網路模型(Dopaminergic neurons model) ,此模型包含1022個代謝物、1131條反應式、48個代謝途徑(如醣酵解、檸檬酸循環、過氧化物質的代謝、酪氨酸代謝系統等)以及六個胞器間隔。
為了探討能量代謝與疾病的關係,我們選用三種目標函數的組合,提供維持神經元細胞所需要的營養攝取物(氧氣、葡萄糖、必需胺基酸…等),且使用通量均衡分析方法(Flux balance analysis, FBA) 得到正常狀態下的通量分布。再利用突變通量均衡分析(Mutant-Flux Balance Analysis, mFBA) 模擬出抑制酪胺酸代謝系統酵素的通量分布,並比較正常與異常情況下通量分布的差異性。

Human brain often associate with massive energy dissipation. When an exception of the energy demand and supply occurs, it is bound to damage the nervous system. Also, it will lose the original function and evolve into Neurodegenerative Disease. Therefore, it takes plenty of time to study this disease. As a result, we hope that we can simulate metabolic flux distribution network by a Genome-scale metabolic model of brain. This research reconstructed the Dopaminergic neurons model by collecting data from bioinformatics database. This model includes 1022 metabolites, 1131 chemical reaction equations, and 48 metabolic pathways. In order to discuss the relationship between the energy metabolism and disease, we provided the nutrients to Dopaminergic neurons to maintain its physiological function. Under these circumstances, we set the three types objective functions, which consists of maximize the flux of ATP synthesis, maximize the flux of NADPH synthesis and minimize the internal flux. We used Flux balance analysis and Mutant-Flux balance analysis to get the flux distribution of network at steady state. We compared the results of perturbations to the fluxes of normal condition, then observed the fluxes with significant difference. We found that the tyrosine metabolism getting abnormal, it will lead the ability of generate energy to decline in the neuronal cells. Also, we observed the flux of Carbon dioxide will be decreased, and the flux of Reactive oxygen species will be increased.
誌謝 I
摘要 II
表目錄 VII
圖目錄 VIII
第一章 緒論 1
1.1前言 1
1.2文獻回顧 5
1.2.1帕金森氏症 5
1.2.2代謝網路模型 9
1.3 研究動機 13
1.4 組織章節 14
第二章 代謝網路生物資料庫及工具程式簡介 16
2.1生物資料庫簡介 16
2.1.1 Kyoto Encyclopedia of Genes and Genomes (KEGG) 16
2.1.2 ExPASy (Expert Protein Analysis System) 19
2.1.3 Recon X 20
2.2工具程式簡介 21
第三章 重建多巴胺神經元細胞代謝網路模型 23
第四章 基於限制條件之代謝模型分析方法 29
4.1數學方法描述 29
4.1.1代謝網路最佳化目標 30
4.1.2代謝網路生理功能目標設定 (Targets setting) 33
4.1.3 內部通量限制 35
4.2 分析方法之介紹 35
4.2.1邊界値上下限之分析(Min-Max bound Analysis) 35
4.2.2通量均衡分析(Flux Balance Analysis, FBA) 37
4.2.3突變通量均衡分析(Mutant-Flux Balance Analysis, mFBA) 38
第五章 多巴胺神經元細胞模型及其應用之結果 39
5.1 酪胺酸系統酵素剔除之模擬結果 39
5.1.1 第一型目標函數 41
5.1.2 第二型目標函數 44
5.1.3 第三型目標函數 47
5.2 模擬結果討論 50
第六章 結論與未來展望 53
6.1 結論 53
6.2 未來展望與建議 53
第七章 參考文獻 55

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