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研究生:沈麗芬
研究生(外文):Li-Fen Shen
論文名稱:探討PAL31在脊髓損傷後發炎反應調控之研究
論文名稱(外文):PAL31 may play an important role as inflammatory modulator in the repair process of the spinal cord injury
指導教授:翟建富翟建富引用關係
指導教授(外文):Kin-Fu Chak
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:101
中文關鍵詞:脊髓損傷發炎反應
外文關鍵詞:PAL31spinal cord injuryinflammation
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由於脊髓損傷之修復機制至目前為止仍未有非常突破性的進展,現今全球投入於脊髓損傷的醫療照護之人力物力非常龐大,因此是一嚴重的醫療課題。哺乳動物的中樞神經一旦損傷,則受傷的神經欲再生的能力便受到限制,但目前科學家仍極力投入有助於神經再生的研究。在1996年鄭宏志博士發表一動物模式,將成鼠胸椎第八節截斷後填入酸性纖維母細胞成長因子及自體肋間神經的修復策略,發現對老鼠下肢的功能性促進有很大的助益,但詳細參與神經再生的機制尚未知。已知cAMP可透過活化下游磷酸激酶Protein kinase A (PKA)進而促進神經突觸的分枝及軸突的再生,然而究竟PKA透過活化何種受質去傳遞下游訊號,在我們的模式中仍未知,因此利用專一性辨認PAK受質的抗體尋找與神經再生相關受質。經比較損傷、修復及正常的老鼠脊髓組織,發現一蛋白質在損傷後大量表現,且在修復組表現量較損傷組低,經由蛋白質純化方式分離此蛋白質,並利用質譜儀解析鑑定為一新穎性蛋白質: PAL31 (Proliferation-associated leucine -rich protein PAL31),利用電腦程式預測亦含有PKA受質磷酸化位。以PAL31抗體偵測發現在脊髓損傷後PAL31總蛋白量即增加,顯示並非在損傷處被大量磷酸化修飾。組織免疫染色結果顯示PAL31表現在損傷中樞部位的巨噬細胞與CD8 T淋巴球,為研究PAL31在發炎反應細胞的功能,建構 PAL31大量表現與抑制細胞株,在大量表現PAL31的RAW 264.7細胞中,經發炎藥物處理後,影響了MCP-1、iNOS與STAT-1的表現量(皆為降低) ,當抑制RAW 264.7細胞表現 PAL31時,發炎藥物處理導致細胞大量死亡現象。本研究結果推論 PAL31為一個在脊髓損傷中被誘導表現之蛋白質,且在發炎反應功能扮演調節者的角色,並可幫助巨噬細胞面對發炎反應藥物刺激時存活。
Spinal cord injury (SCI) is a costly disease to treat in every medical care system of the world. The limited re-growth of injured nerve fibers in the mammalian Central Nervous System (CNS) has been known since the turn of the century. Despite the fact that functional regeneration in a complete T8 transection model has been reported (Cheng et al., 1996. Science 273, 510-513), the mechanism and signaling pathway involved in spinal cord regeneration still remains to be elucidated. It is known that cAMP promotes neurite outgrowth and axon regeneration through activation of protein kinase A (PKA). In order to identify the specific PKA substrates induced after spinal cord injury (SCI), we have screened the specific PKA substrates present in damaged tissue using antibody that specifically recognizes the phospho-substrate motif. Our results indicated that a 30 kDa protein was substantially induced at six days after SCI. However, the induction of the transducing signal was reduced in samples treated with acidic fibroblast growth factor (aFGF, also known as FGF-1) after the lesion was transplanted with intercostal nerve. The 30 kDa protein was purified and identified by mass spectrometry as a novel protein, PAL31. The results of immunohistochemical study showed that PAL31 is abundantly expressed in the epicenter of the injured spinal cord and colocalizes with ED1 positive cells (macrophages) and CD8 T lymphocytes. Overpression of PAL31 in RAW 264.7 cells resulted in the down regulation of MCP-1、 iNOS and STAT-1. However, knockdown of PAL31 by siRNA seems to lead to apoptosis when the cells were treated with inflammatory inducer. These experimental results suggest that PAL31’s novel functions may involve the modulation of the inflammatory response during SCI and, at the same time, this PAL31 may play an important role in maintaining the survival of macrophage in the presence of inflammatory stress.
中文摘要 1
英文摘要 2
第一章、緒論 4
一、神經再生醫學研究之現況 4
二、本研究使用之神經修復組別應用的策略 5
三、發炎反應在脊髓損傷中的研究 7
四、PAL31基本介紹 9
五、磷酸激酶在神經再生研究的重要性 11
六、CAMP及PROTEIN KINASE A在神經再生的研究 12
七、研究目的與策略 13

第二章、實驗材料與方法 15
一、實驗動物與細胞株 15
二、老鼠脊髓損傷與修復手術 15
三、PAL31免疫血清製備 16
四、PAL31 免疫沈澱實驗 17
五、陰離子交換樹脂管柱純化 17
六、蛋白質定量 18
七、西方墨點實驗 18
八、PHOSPHATASE 處理蛋白質樣品 19
九、二維蛋白質電泳步驟 19
十、利用質譜儀進行蛋白質身分鑑定 20
十一、組織免疫染色 22
十二、PAL31大量表現與抑制細胞株建立 22
十三、發炎反應蛋白質晶片應用 24
十四、即時定量聚合酶鏈式反應 25
十五、CASPASE 3 酵素活性分析 26
十六、TUNEL ASSAY 26

第三章、實驗結果 28
一、磷酸化PAL31在脊髓損傷動物模式中損傷區域脊髓組織之蛋白質表現量 28
二、PAL31為PKA受質 (PKAS1) 之確認實驗 31
三、PAL31的表現量與PKAS1一致 31
四、磷酸化PAL31(PKAS)及PAL31蛋白質在成鼠脊髓與腦的蛋白質表現量 32
五、PAL31在脊髓損傷組織的分布 32
六、脊髓損傷中由巨噬細胞與CD8淋巴球表現PAL31 33
七、PAL31大量表現時影響MCP-1、INOS 與STAT-1的表現量 34
八、抑制PAL31表現導致巨嗜細胞在發炎藥物刺激時死亡率增加 37

第四章、討論 39
一、結合傳統蛋白質純化技術與質譜儀鑑定 PAL31 為一脊髓損傷後誘導性表 現蛋白質 39
二、PAL31 在脊髓損傷中可能扮演的角色 40
三、MCP-1、STAT-1、iNOS在發炎反應中的基本介紹與PAL31之關係討論
42
四、PAL31 在發炎反應中可能扮演調節者 (MODULATOR)的角色 47
五、PAL31影響發炎反應細胞存活率的探討 48
六、PAL31磷酸化修飾現況 49
七、總結 49
第五章、參考文獻 51~61
第六章、圖 62~85
第七章、附錄 86
一、附圖 86
二、發表論文 87~97
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