2011-01-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/681629摘要：介白質6是一種具有多功能的細胞激素，並在發炎過程中扮演主要角色。介白質6的過量表現已經被證明會引起許多發炎性自體免疫疾病，例如：類風濕性關節炎、青少年不明原因性關節炎。此外,在許多人類腫瘤發生過程及腫瘤相伴症候群中，介白質6也扮演重要的角色。所以，可以抑制介白質6作用的物質將有機會被利用來治療這一類的疾病。介白質6屬於共用醣蛋白130激素受體次要單元的激素家族。在介白質6受體系統中,細胞膜上的介白質6受體(醣蛋白80)和溶解型的介白質6受體藉由與醣蛋白130之間交互作用一起調節傳遞至細胞內的介白質6訊息傳導。針對於介白質6和介白質6受體之間的訊息傳導,我們利用噬菌體胜肽表現資料庫快速搜尋針對介白質6受體的胜肽受質,已經成功地找出新的胜肽。我們證明這樣挑選出的反應性受質(S7胜肽)可以抑制腫瘤的血管新生和生長。在本計畫中,我們將要去加強這個抑制性胜肽,改善它對人類介白質6受體的專一性與親和性並且探討它在臨床治療的可能應用。本計畫的加強程序是根據介白質6受體的結構,分別利用分子模型及模擬篩選去改造此胜肽,而改造的胜肽將在活體外測試其介白質6訊息傳導抑制能力以及在活體內進行其治療潛力的實驗。<br> Abstract: Interleukin (IL)-6, a pleiotropic cytokine with varied systemic functions, plays a major role in inflammatory processes. Overproduction of IL-6 has been shown to play a role in inflammatory autoimmune diseases such as rheumatoid arthritis, and juvenile idiopathic arthritis. Moreover, IL-6 also critically involves in the carcinogenesis of various human cancers as well as paraneoplastic syndrome. An agent blocking IL-6 actions can therefore be a therapy of these diseases. IL-6 belongs to a cytokine family, which shares the cytokine receptor subunit glycoprotein (gp) 130. In the IL-6 receptor (IL-6R) system, both a membrane-bound IL-6R (gp80) and a soluble form of IL-6R are able to mediate IL-6 signals into the cells through the interaction of gp130. To target IL-6/IL-6R (gp80) signaling, we have successfully identified a novel peptide using rapid screening of selective peptide ligands against IL-6R with a phage display peptide library. We have demonstrated that this selective interactive ligand (S7 peptide) is valid for inhibiting tumor angiogenesis and tumor growth. In this project, we are going to refine this inhibitory peptide to improve its affinity and specificity to human IL-6R and to unveil its potential application in clinical therapeutic indications. A refinement procedure based on the structure of IL-6R is proposed. The procedure utilized both molecular modeling and virtual screening, and the resulting modified hit peptides will be tested both in vitro for their IL-6 signaling inhibitory activity and in vivo for their therapeutic indications.介白質6胜？藥物IL-6peptide drug