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研究生:巫志鴻
研究生(外文):Wu, Chih-Hung
論文名稱:啟動子-核糖體結合位庫的建立與基因電路規格設計上的應用
論文名稱(外文):Construction of Promoter-RBS Libraries and Its Application to Gene Circuit Design with Design Specifications
指導教授:陳博現
指導教授(外文):Chen, Bor-Sen
口試委員:黃宣誠張翔鄭桂忠莊永仁藍忠昱莊哲男林俊良陳博現
口試日期:2012-2-22
學位類別:博士
校院名稱:國立清華大學
系所名稱:電機工程學系
學門:工程學門
學類:電資工程學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:108
中文關鍵詞:合成生物學基因電路H2/H∞參考追蹤設計
外文關鍵詞:synthetic biologygenetic circuitH2/H∞ reference tracking design
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合成生物學的主要目的,在於設計一個具備特定功能的合成基因電路。在設計之初先提出其設計規格,再將此基因電路加以實現,免除一系列複雜的實驗。然而,到目前為止,要達到此目標還有很長的一段路要走。其最主要的原因,在於缺乏一些具有良好特性化的生物元件及設計的方法,使得合成生物學家無法彷照電機、機械工程師的設計步驟來加以設計合成基因電路。於是,為了奠定基因電路設計的基礎,我們便藉由系統鑑別的技術來將生物元件特性化。於是,要如何建立一個合成基因電路上可以使用的生物元件庫便是一個很重要的課題。
啟動子和核糖體結合位分別影響了基因轉錄及轉譯的效率,然而由於轉錄效率相對於轉譯效率而言十分快速,使我們不易建立其各別獨立的分子生物庫。於是,我們將這兩個生物元件考慮成一個整合的元件,再藉由系統鑑別系統的技術來鑑別出啟動子-核糖體結合位元件的強度,再以強度建立一個有用的啟動子-核糖體結合位庫。而此啟動子-核糖體結合位庫的建立,將可協助我們免除不斷試誤的過程便設計出所需求的合成基因電路。一般而言,我們必須建立三種啟動子-核糖體結合位庫,即連續表現型、抑制子調控型及促進子調控型。我們提供了這三種啟動子-核糖體結合位庫的建立方式,並提供一個系統化的方法來協助我們選擇適合的啟動子-核糖體結合位元件,使得選擇出來的元件能夠使基因電路具備我們欲求之行為。基於本論文提出的啟動子-核糖體結合位庫的建立方式及系統化的設計方法,經設計者提出幾個設計的規格後,便可使用本論文所提出的系統化設計方法,利用已建立好的啟動子-核糖體結合位庫,將設計基因電路的工作變成容易,而使用者不再需要試誤的實驗過程。基於啟動子-核糖體結合位庫的建立及系統化的設計方法的提出,在未來,合成生物學家便可將設計基因電路的心力直接放在以應用導向的基因電路上,以大幅縮短基因電路的設計周期,使得以工程方法設計基因電路的目的得以實現。
A major goal of synthetic biology is to engineer synthetic gene circuits with desired behaviors. Up to now, however, it still requires extensive and iterative work. The main obstacle is the lack of some well-characterized biological parts and design methods. By the identification technique, the biological parts can be well-characterized to build a useful library for engineering a novel gene circuit. Hence how to build a useful library of biological parts for engineering synthetic gene circuit in vitro and in silico is an important topic from the viewpoint of synthetic biology.
Promoters and RBSs are regarded as a lumped component in this study so that the promoter-RBS component can help us construct useful promoter-RBS libraries by the identification technique. The promoter-RBS libraries can be easily used to engineer a synthetic gene circuit before laborious process of trial-and-error. In general, there exist 3 kinds of promoter-RBS components in synthetic biology, hence 3 kinds of promoter-RBS libraries are constructed in this study, i.e., constitutive, repressor-regulated and activator-regulated promoter-RBS libraries.We provide the construction procedure for the constitutive, repressor-regulated, and activator-regulated promoter-RBS libraries. After building 9 promoter-RBS libraries, we provide the characteristic indexes of these libraries through their mathematical models, a systematic method is proposed to help us select the adequate promoter-RBS component set. Finally, we provide a library-based search method to help us quickly select the most adequate promoter-RBS component set from promoter-RBS libraries. The proposed library-based search method can reduce the number of trial-and-error experiments in selecting an adequate promoter-RBS component set for a synthetic gene circuit, and then a gene circuit can be predictably implemented by a systematic design method before trial-and-error experiments.
摘 要 i
Abstract iii
致 謝 v
Contents vii
List of figures ix
List of tables 1
1. Introduction 1
2. Construction of Promoter-RBS Libraries 9
2.1. Characteristic Indexes of Promoter-RBS libraries based on promoter-RBS strength 10
2.2. Dynamic model for protein expression of synthetic gene circuit 14
2.3. Construction of constitutive promoter-RBS library 17
2.4. Construction of repressor-regulated promoter-RBS libraries 21
2.5. Construction of activator-regulated promoter-RBS libraries 27
3. Synthetic gene circuit model based on the gene circuit topology 31
3.1. Promoter-RBS regulation function for promoter-RBS libraries 32
3.2. Construction of synthetic gene circuit based on circuit topology 37
4. Synthetic gene circuit design based on the systematic method 42
4.1. Multiobjective reference tracking design with noise attenuation level and optimal reference tracking 43
4.2. Design procedure of multiobjective reference tracking design 46
5. Design of in silico and experimental examples based on the promoter-RBS libraries 56
5.1. Simple synthetic transcriptional cascade 57
5.2. Synthetic toggle switch design 60
6. Discussion 63
7. Conclusion 68
Appendix 71
Bibliography 81
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