English  |  正體中文  |  简体中文  |  Items with full text/Total items : 54371/62179 (87%)
Visitors : 8913715      Online Users : 101
RC Version 6.0 © Powered By DSPACE, MIT. Enhanced by NTHU Library IR team.
Scope Tips:
  • please add "double quotation mark" for query phrases to get precise results
  • please goto advance search for comprehansive author search
  • Adv. Search
    HomeLoginUploadHelpAboutAdminister Goto mobile version
    National Tsing Hua University Institutional Repository > 生命科學院  > 分子與細胞生物研究所 > 博碩士論文  >  尋找可調節家族性原發皮膚類澱粉沉積症MCP-1蛋白表現量之藥物


    Please use this identifier to cite or link to this item: http://nthur.lib.nthu.edu.tw/dspace/handle/987654321/85638


    Title: 尋找可調節家族性原發皮膚類澱粉沉積症MCP-1蛋白表現量之藥物
    Authors: 何建鋕
    Ho, Chien-Chih
    Description: GH02101080609
    碩士
    分子與細胞生物研究所
    Date: 2014
    Keywords: 家族性原發皮膚類澱粉沉積
    Familial Primary Cutaneous Amyloidosis (FPCA);amyloidosis;protein misfolding;IL-31 receptor;IL-31RA;MCP-1;MEK1/2;STAT1
    Abstract: 家族性原發性皮膚類澱粉沉積症 (Familial primary cutaneous amyloidosis, FPCA) 一種好發於東南亞及南美的慢性皮膚病,近年來已發現FPCA是由於角質細胞的IL-31 receptor-IL-31RA或oncostatin M receptor beta (OSMRb) subunit發生點突變而造成。一般皮膚角質細胞在受到IL-31的刺激時會促使MCP-1產生並吸引單核球及巨噬細胞來清除皮膚的細胞碎片,但當IL-31 receptor發生突變後,MCP-1的產生量會下降而導致細胞碎片無法清除,最後累積而造成皮膚類澱粉沉積的現象發生。FPCA現有的治療方法以塗抹外用類固醇 (corticosteroids) 及服用抗組織胺藥物為主,但病症大多有復發的情形。
    在本篇研究中建立了以人類皮膚角質細胞 (HaCaT) 轉殖mutant IL-31RA的細胞株作為一個篩藥平台,用以找出可提升IL-31RA突變細胞株中MCP-1的藥物,進而達到改善家族性原發性皮膚類澱粉沉積症的目的,並進一步確認藥物的作用機制。
    在藥物篩選結果發現MEK1/2 kinase inhibitor可提升IL-31RA突變細胞MCP-1產量。此外,上市的MEK1/2 kinase inhibitor, Trametinib, 也能夠提升IL-31RA突變細胞MCP-1產量;除了MCP-1產量以外,MCP-1 mRNA表現量在加入藥物後同樣有看到提升的現象。而MCP-1 promoter的轉錄因子之一- phospho-STAT1 (Tyr 701) 在加入藥物後,發現表現量有顯著增加的情形。
    根據這些結果可推測藉由抑制MEK1/2的活性會增加phospho-STAT1 (Tyr701) 的表現,phospho-STAT1 (Tyr701) 作為transcription activator結合到MCP-1 promoter增加MCP-1 mRNA的表現量,進而提升IL-31RA突變細胞的MCP-1產量,顯示MEK1/2在調控IL-31RA突變細胞的MCP-1產量扮演著相當重要的角色,未來期待能更進一步研究MEK1/2與家族性原發型皮膚類澱粉沉積症的關聯性,也期待與現有療法搭配能更有助於疾病的改善與減少復發的情形
    Primary cutaneous amyloidosis (PCA) is a chronic skin disease that most frequently occurs in Southeast Asia and South America. Based on the etiology, PCA can be classified into sporadic and familial types. Recently, mutations on IL-31RA or oncostatin M receptor β (OSMRβ) gene have been found to correlate with familial primary cutaneous amyloidosis (FPCA). MCP-1, upon induction by IL-31 can recruit monocytes/macrophages to clean the cell debris on the skin. However, when certain mutations occur in IL-31 receptor, the levels of MCP-1 would decrease, leading to the accumulation of cell debris on the surface of skin.
    In this study, a cell-based drug screening system was established in which human keratinocyte cells (HaCaT) were transfected with mutant IL-31RA plasmid. In lieu of this system, several potential activators of MCP-1 in IL-31RA mutant cells were discovered. Subsequently, the underlying mechanism was explored.
    Results from this study showed that the levels of MCP-1 were increased by MEK1/2 kinase inhibitors, PD 198306 or Trametinib. The expression levels of MCP-1 mRNA increased when the cells were treated with PD 198306. The expression levels phospho-STAT1 (Tyr701), one transcription factor of MCP-1 promoter, were also significantly increased when the HaCaT cells harboring mutant IL-31RA were treated with either MEK1/2 kinase inhibitors.
    Overall, these results might suggest that inhibition of MEK1/2 activity might increase the expression levels of phospho-STAT1 (Tyr701). The phospho-STAT1 (Tyr701) can act as a transcription activator and bind on MCP-1 promoter to enhance the transcription. Although the exact interplays between MEK1/2 and FPCA remains to be further investigated, this study indicate that MEK1/2 pathway may be a novel target for development of effective FPCA treatment.
    URI: http://nthur.lib.nthu.edu.tw/dspace/handle/987654321/85638
    Source: http://thesis.nthu.edu.tw/cgi-bin/gs/hugsweb.cgi?o=dnthucdr&i=sGH02101080609.id
    Appears in Collections:[分子與細胞生物研究所] 博碩士論文

    Files in This Item:

    File SizeFormat
    GH02101080609.pdf171KbAdobe PDF215View/Open


    在NTHUR中所有的資料項目都受到原著作權保護,僅提供學術研究及教育使用,敬請尊重著作權人之權益。若須利用於商業或營利,請先取得著作權人授權。
    若發現本網站收錄之內容有侵害著作權人權益之情事,請權利人通知本網站管理者(smluo@lib.nthu.edu.tw),管理者將立即採取移除該內容等補救措施。

    SFX Query

    與系統管理員聯絡

    DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - Feedback