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| 題名: | 探討結締組織生長因子CTGF刺激單核球細胞所需之細胞表面分子 |
| 作者: | 邵彥豪 |
| 貢獻者: | 醫學科學研究所 |
| 關鍵詞: | 結締組織生長因子 單核球細胞 |
| 日期: | 2010 |
| 上傳時間: | 2010-10-20 12:43:20 (UTC+8) |
| 摘要: | 結締組織生長因子，屬於分泌型蛋白CCN家族的一員，在細胞及細胞外基質交互作用中扮演重要的角色，其主要功能在於調控細胞分化、增生、黏附、移動、凋亡、纖維化、血管新生及胞外基質的生成等；在本實驗室先前的研究中已知，結締組織生長因子會引發人類CD14+單核球細胞提升IL-8的分泌。然而，結締組織生長因子如何從胞外傳遞訊息至胞內活化訊息傳遞路徑的過程目前尚不清楚，是否經由細胞表面的醣類或特殊受體亦未可知。在此我們檢視細胞表面的醣類fibronectin、heparin和heparan sulfate與CTGF的交互作用，發現Heparin sulfate proteoglycans參與CTGF之刺激作用。為了進一步鑑定其受體，首先以integrin ??2次單位的拮抗性抗體來觀察細胞膜上的integrin是否為CTGF的特殊受體；而後使用TrkA磷酸化的抑制劑K-252a，檢視TrkA是否參與CTGF引發IL-8分泌過程；最後利用乳鐵蛋白與CTGF競爭LRP1結合位置以辨別LRP1之重要性。為了解CTGF是否經由胞吞作用來傳遞訊息，使用胞吞作用的抑制劑Phenylarsine Oxide及核內體抑制劑NH4Cl以觀察其對CTGF刺激細胞產生IL-8之影響。結果顯示在人類CD14+單核球細胞中，CTGF可能藉由結合LRP1及TrkA，並利用胞吞作用進入細胞，經過核內體的消化代謝後，接著活化p38、ERK及JNK的MAPK訊息傳導路徑，最終刺激IL-8的分泌提升。
Connective Tissue Growth Factor (CTGF), is one member of secretory protein CCN family that mediates the interaction of cell surface and extracellular matrix (ECM). Among the many function of CTGF are angiogenesis, adhesion, osteogenesis, tissue repair, fibrosis, proliferation, migration, and differentiation, CTGF is also a pathogenic factor in variety of fibrotic disorders. In our previous study, CTGF has been found to induce IL-8 secretion on human CD14+ monocytes. However, the signal transduction pathway of CTGF and the specific receptor recognized by CTGF on human monocytes are still poorly understood. In this study, we investigated the interaction between surface fibronectin, heparin, heparan sulfate and CTGF, found heparin sulfate proteoglycans involved in CTGF function. To further identify the receptor of CTGF, we used antagonist of integrin ??2 to define whether integrin ??2 is the specific receptor for CTGF. Then we utilized TrkA inhibitor K-252a to identify whether TrkA participate in the IL-8 secretion pathway induced by CTGF. Finally we used lactoferrin competed with CTGF binding to LRP1 to clarifying whether LRP1 is the receptor for CTGF. Furthermore, we utilized additional endocytosis inhibitor Phenylarsine Oxide and endosome inhibitor NH4Cl to identify whether IL-8 induction through endocytosis. Data suggested that on human CD14+ monocytes, CTGF might bind to LRP1 and TrkA then internalized into cells by endocytosis, combined with endosome then activated MAP Kinase p38, ERK and JNK eventually increased IL-8 secretion. |
| 關聯: | 75頁 |
| 描述: | 謝誌 4
摘要 5
Abstract 6
縮寫 7
引言 9
一、CCN蛋白與結締組織生長因子CCN2/CTGF 9
1. CCN蛋白家族 9
2. CCN家族的功能 10
3.結締組織生長因子CCN2/CTGF 13
二、Heparin Sulfate Proteoglygans（HSPGs） 15
三、Integrins 16
四、TrkA（Tropomyosin-related kinase A） 17
五、LRP（LDL Receptor-related Protein） 18
六、CXCL8/Interleukin-8（IL-8） 19
動機與目的 21
材料與方法 22
A、材料 22
一、試劑與溶液 22
二、培養基與培養液 28
三、抗體 28
B、方法 29
一、細胞培養 29
二、人類CD14+單核球細胞純化 29
三、流式細胞儀分析（Flow Cytometry Analysis） 30
四、IL-8 Enzyme-Linked Immunobent Assay（ELISA） 30
五、細胞溶質的收集 31
六、BCA assay蛋白質定量分析 31
七、西方墨點法（Western Blotting） 32
八、雷射共軛焦顯微鏡（Confocal Microscopy） 33
實驗結果與分析 35
一、Glycosamonoglycans可與CTGF產生交互作用 35
二、Heparinase對CTGF刺激人類CD14+單核球細胞分泌IL-8的影
響 36
三、Integrin subunit ??2不參與CTGF刺激IL-8分泌的過程 37
四、TrkA不會影響CTGF刺激IL-8的分泌提升 37
五、LRP可結合CTGF參與刺激IL-8分泌的過程 38
六、由螢光顯微鏡證實CTGF會藉由胞吞作用進入到單核球內 38
七、胞吞作用的抑制劑PAO可抑制CTGF對人類CD14+單核球細胞
的刺激 39
八、CTGF刺激IL-8分泌上升須經由Endosome 40
九、CTGF經由活化p38、ERK及JNK誘發IL-8分泌 40
討論 42
附圖 49
參考文獻 67
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