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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳林祈(Lin-Chi Chen) | |
| dc.contributor.author | Yeh-Hsing Lao | en |
| dc.contributor.author | 勞業興 | zh_TW |
| dc.date.accessioned | 2021-06-15T04:48:20Z | - |
| dc.date.available | 2012-08-06 | |
| dc.date.copyright | 2010-08-06 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-04 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45896 | - |
| dc.description.abstract | 如何篩選具有功能性之核酸適體是目前相關領域研究中一個重要的課題，本研究即提出一種新穎的核酸適體篩選方法，利用競爭標的蛋白之功能性結合位方式篩選核酸適體，以此獲得具功能性之核酸適體，故此法稱為結合位特異性系統配位子指數增益演繹程序(ES-SELEX)。本研究以人類流感(A/New Caledonia/20/99)血液凝集素做為標的蛋白，並利用前述方法篩選具有抑制血液凝集素功能之核酸適體。經過九個回合篩選後，可獲得對血液凝集素高度親和性之核酸適體，其平均解離常數可達1.2 nM，其中編號CP9P536之核酸適體被確認具有血液凝集素抑制功能，該核酸適體於62.5至1000 nM濃度中可完全抑制血液凝集素活性。除此之外，在免疫沉澱試驗中亦驗證該核酸適體能於人類血清及流感抗原中辨識流感血液凝集素，顯現該核酸適體除具高度親和力外並具專一性。在核酸適體結構上，利用圓二色性分析推測CP9P536核酸適體的結構屬於平行鳥糞嘌呤四面體之複合結構，同時該核酸適體在攝氏4度至37度間結構相當穩定。由實驗結果可以發現，本研究所提出之結合位特異性核酸適體篩選方法，不但可獲得高度專一性之核酸適體，更可以直接且快速獲得具有預期功能之核酸適體，並且由本方法所篩選出之核酸適體具有高度結構穩定之特性，可供未來進一步發展相關流感抑制藥物之應用。 | zh_TW |
| dc.description.abstract | Antagonistic aptamer selection is an important issue in the field of aptamer study. In this thesis, a novel methodology of aptamer selection is designed and proposed. This method is called epitope-specific SELEX (systematic evolution of ligands by exponential enrichment), in which antagonistic aptamers are obtained by the SELEX with competition for the receptor-binding epitope on a target protein. Hemagglutinin of human influenza A/New Caledonia/20/99 is chosen as a model to demonstrate this strategy. After nine SELEX rounds, anti-hemagglutinin aptamers with high affinity are obtained, and the mean dissociation constant of the aptamer pool is as low as 1.2 nM. In the aptamer pool, aptamer CP9P536 shows high antagonistic activity against hemagglutinin. It can inhibit the agglutination activity of hemagglutinin with the concentration range from 62.5 to 1000 nM. Furthermore, the specificity of this aptamer is identified by the immunoprecipitation assay, which shows that the aptamer can recognize hemagglutinin in human serum and viral antigen. Also, the structure of CP9P536 is characterized by circular dichroism. It is supposed that the structure of CP9P536 is a parallel G-quadruplex structure. Moreover, CP9P536 is structurally stable between 4 to 37°C. As a result, it is considered that ES-SELEX can effectively screen the aptamer with high affinity and desired functionality. Moreover, the aptamer identified and characterized in this study is structurally stable for clinical applications. It has potential for DNA-based anti-influenza drug development. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T04:48:20Z (GMT). No. of bitstreams: 1 ntu-99-R96631004-1.pdf: 3701742 bytes, checksum: c319738144c2d72c125ef796dcff2e49 (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 誌謝 (Acknowledgement) i
中文摘要 (Chinese abstract) iii Abstract v Contents vii List of Figures xi List of Tables xiii Chapter 1 Introduction 1 1.1 Description of the present study 1 1.2 Objectives of the thesis 2 1.3 Strategy of this thesis 3 Chapter 2 Literature Review 5 2.1 SELEX technology and aptamers 5 2.1.1 Introduction 5 2.1.2 Modification and improvement of SELEX technology 7 2.2 Introduction of human influenza 12 2.2.1 Human influenza 12 2.2.2 Hemagglutinin 13 2.2.3 Influenza or hemagglutinin inhibitors 15 2.3 Aptamers for influenza inhibition or detection 16 Chapter 3 Material and Methods 21 3.1 Apparatus and reagents 21 3.2 Screening of antagonistic aptamer against hemagglutinin by ES-SELEX 23 3.3 Aptamer and target consideration 27 3.3.1 Aptamer library design and synthesis 27 3.3.2 Hemagglutinin subunit 1 (HA1) 28 3.4 Single-stranded DNA pre-treatment 30 3.5 Protein-specific selection 31 3.5.1 HA1/ssDNA binding 31 3.5.2 Washes 31 3.5.3 Elution of aptamer candidates 32 3.6 Epitope-specific selection 33 3.7 Counter selection 33 3.7.1 Counter selection against His-tag affinity column 34 3.7.2 Counter selection against fetuin and HSA 34 3.8 DNA amplification and single strand isolation 35 3.8.1 Quantitation of eluted ssDNA by qPCR 35 3.8.2 ssDNA amplification by conventional PCR 35 3.8.3 Single-stranded DNA isolation 36 3.9 Sequencing for aptamer candidates 37 3.10 Characterization of anti-hemagglutinin aptamers 37 3.10.1 Affinity assay with MWCO columns 38 3.10.2 Affinity assay by SPR 38 3.10.3 Hemagglutinin-inhibition assay 39 3.10.4 Circular dichroism (CD) measurement 40 3.10.5 Binding motif determination by aptamer microarray 41 Chapter 4 Results and Discussion 43 4.1 Screening for aptameric hemagglutinin antagonists by ES-SELEX 43 4.1.1Protein-specific selection 43 4.1.2 Epitope-specific selection 45 4.1.3 Aptamer enrichment via ES-SELEX 47 4.2 Characterization of anti-HA aptamers 53 4.2.1 Affinity evaluation of anti-HA aptamers in fraction CP9P5 53 4.2.2 Classification of anti-HA aptamers from fraction CP9P5 55 4.2.3 Functional screening for hemagglutinin antagonistic aptamers 56 4.3 Aptamer CP9P536: An antagonist of hemagglutinin 67 4.3.1 Antagonistic evaluation of CP9P536 67 4.3.2 Pull-down assays with CP9P536 69 4.3.3 Structural analysis of CP9P536 by circular dichroism 70 Chapter 5 Conclusions 81 References 83 Appendix 89 | |
| dc.language.iso | en | |
| dc.subject | 人類流感 | zh_TW |
| dc.subject | 結合位特異性系統配位子指數增益演繹程序 | zh_TW |
| dc.subject | 核酸適體 | zh_TW |
| dc.subject | 血液凝集素 | zh_TW |
| dc.subject | Epitope-specific SELEX | en |
| dc.subject | human influenza | en |
| dc.subject | hemagglutinin | en |
| dc.subject | aptamers | en |
| dc.title | 利用結合位特異性SELEX法篩選具抑制流感凝集素功能之DNA適體 | zh_TW |
| dc.title | Screening of Functional DNA Aptamers Capable of Influenza Hemagglutinin Inhibition by Epitope-Specific SELEX | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 白果能(Konan Peck) | |
| dc.contributor.oralexamcommittee | 陳倩瑜(Chien-Yu Chen),張翼中(Yi-Chung Chang) | |
| dc.subject.keyword | 結合位特異性系統配位子指數增益演繹程序,核酸適體,血液凝集素,人類流感, | zh_TW |
| dc.subject.keyword | Epitope-specific SELEX,aptamers,hemagglutinin,human influenza, | en |
| dc.relation.page | 93 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-08-04 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 生物產業機電工程學研究所 | zh_TW |
| 顯示於系所單位： | 生物機電工程學系 | |
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