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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳垣崇(Yuan-Tsong Chen) | |
| dc.contributor.author | Chih-Wen Ou Yang | en |
| dc.contributor.author | 歐陽志玟 | zh_TW |
| dc.date.accessioned | 2021-06-13T06:37:54Z | - |
| dc.date.available | 2010-08-12 | |
| dc.date.copyright | 2005-08-12 | |
| dc.date.issued | 2005 | |
| dc.date.submitted | 2005-07-28 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34972 | - |
| dc.description.abstract | Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are related life-threatening cutaneous adverse reactions most often caused by medication. Carbamazepine (CBZ), a commonly prescribed anticonvulsant, is the number one culprit drug associated with SJS in Taiwan, accounts for 25% of all drug-induced SJS.
Susceptibility to drug induced idiosyncratic reactions is thought to be genetically determined and immune-mediated. Previous studies suggest that the pathogenesis of the severe cutaneous adverse drug reactions involves MHC-restricted presentation of a drug or its metabolites for T-cell activation. However, the specific MHC molecules involved are not known until our study of carbamazepine-induced SJS/TEN in which we identified HLA-B*1502 as the MHC molecule. To further investigate the pathogenesis mechanism, we hypothesized that CBZ or its metabolites bind to endogenous proteins through processing and complexed with HLA-B*1502 or directly bind to the HLA-B*1502-bound peptides, which are then recognized by T-lymphocytes. The specific aims of my thesis are: 1. Establishment of the soluble HLA-B*1502-producing stable clones. 2. Identification of the peptides bind to the HLA-B*1502. 3. Identification of the drug-modified peptides involved in CBZ-SJS. Using soluble HLA-B*1502 molecule as a bait, I identified over 100 peptides bind to the HLA-B*1502. An unusual and an unique feature of these peptides were that many of these endogenous bound peptides (up to 20.9 %) contained polyproline, ranged from 4 to 9 continuous proline residues, but typically 6, 7 or 8 proline residues in the peptides. There were a total of 38 different proline-rich peptides been identified. Among these peptides, the existence of continuous proline residues in the center was a consistent finding; amino acid residues at the N- or C- terminal of peptides were variable. Interestingly, in the presence of CBZ, these proline-rich peptides decreased dramatically. We hypothesized that CBZ may bind to the polyproline peptides covalently, which modify them to become unnatural peptides thus unable to be recognized as the proline-rich peptides under analysis of LC/MS/MS and SEQUEST program. Further functional studies will be needed to demonstrate that these CBZ-modified peptides are indeed involved in the induction of T cell activation in both drug and peptide-specific manners. This is the first study in identification of the MHC-bound peptides associated with adverse drug reactions. The discovery opened a door to understanding the complete mechanism of this life-threatening condition. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T06:37:54Z (GMT). No. of bitstreams: 1 ntu-94-R92445101-1.pdf: 2454295 bytes, checksum: eb19b7beda8f52f21666fc95ba6c9f41 (MD5) Previous issue date: 2005 | en |
| dc.description.tableofcontents | Abstract 1
Introduction 3 Materials&Methods 15 Results 30 Discussion 45 Figures 54 Tables 74 References 91 | |
| dc.language.iso | en | |
| dc.subject | 藥物不良反應 | zh_TW |
| dc.subject | adverse drug reactions | en |
| dc.subject | carbamazepine | en |
| dc.subject | antigen骯 | en |
| dc.subject | HLA | en |
| dc.title | Pathogenesis of carbamazepine-induced Stevens-Johnson Syndrome :
Identification of the drug-modified peptides bind to the HLA-B*1502 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳鈴津,陶密華,鄔哲源 | |
| dc.subject.keyword | 藥物不良反應, | zh_TW |
| dc.subject.keyword | adverse drug reactions,carbamazepine,antigen骯,HLA, | en |
| dc.relation.page | 95 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2005-07-28 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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