提昇私校研發能量專案計畫---自體免疫疾病中心之建立---子計畫三：探討第二型轉麩胺脢在清除凋亡細胞時所扮演的角色(III)

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Title:	提昇私校研發能量專案計畫---自體免疫疾病中心之建立---子計畫三：探討第二型轉麩胺脢在清除凋亡細胞時所扮演的角色(III) Role of Transglutaminase 2 in the Clearance of Apoptotic Cells (III)
Authors:	黃建寧 Chien-ning, Huang
Contributors:	中山醫學院醫學系
Keywords:	紅班性狼瘡;殼胺醯胺轉移脢;自體抗原;凋亡 Systemic lupus erythematosus (SLE);Transglutaminase 2 (TG2);Autoantigen;Apoptosis
Date:	2007
Issue Date:	2010-11-25T03:11:12Z (UTC)
Abstract:	紅班性狼瘡的致病原因已知和許多因子有關，但是其分子機制仍未被完全瞭解，目前相信凋亡細胞的清除不全，是自體抗原產生的重要因素。第二型殼胺醯胺轉移脢是一種具有轉胺活性的多功酵素，而且也被發現參與在細胞凋亡及後續之凋亡細胞的清除，本計劃就是要釐清第二型殼胺醯胺轉移脢在紅班性狼瘡的致病機轉中的角色。在第一年我們檢測第二型殼胺醯胺轉移脢的表現。兩種類似紅班性狼瘡症狀及一種對照組的老鼠將分為兩組，分別於6 週齡及24 週齡時採集巨嗜細胞及不同部位器官組織，包括心、肝、脾、肺、腎、肌肉。第二型殼胺醯胺轉移脢的表現將以反轉錄聚合脢鏈反應及免疫墨點法偵測。結果發現在狼瘡鼠中，雖然第二型殼胺醯胺轉移脢的表現在不同組織器官中的表現量不同，但是在紅班性狼瘡小鼠發病前後並無不同。第二型殼胺醯胺轉移脢, 本身為一個需鈣離子之轉胺甲醯轉移脢﹐也被證實牽涉在紅斑性狼瘡的致病基轉中。所以在第二年我們分析狼瘡鼠之巨嗜細胞的吞噬能力，與第二型殼胺醯胺轉移脢活性。結果發現類狼瘡鼠之巨嗜細胞的吞噬能力﹐跟對照之正常小鼠比較﹐有明顯的下降。而且跟第二型殼胺醯胺轉移脢活性有關。為了找出更確切的原因﹐第三年度則針對狼瘡模式小鼠的巨嗜細胞﹐找出可能造成吞噬能力下降的原因。我們的實驗結果發現﹐粒線體相關路徑的細胞凋亡蛋白﹐在狼瘡模式小鼠有較明顯增加。這些發現也說明小鼠之巨嗜細胞的吞噬能力較低是因為自身凋亡所致，而不是第二型殼胺醯胺轉移脢表現上的缺失所致。 The pathogenesis of SLE is certainly determined by multiple factors, but the molecular mechanisms have not been completely characterized. In recent reports, incompetence in the clearance of apoptotic cells has been demonstrated as an important factor in autoantigen production, but the mechanism is still unclear. Transglutaminase 2 (TG2) is a multi-functional protein with transamidating activity, and has been reported involving in apoptosis and the subsequent clearance process. In this 3-years project, we intend to elucidate the association between TG2 and the clearance of apoptotic cells in SLE. The purpose of the first year is examining the expression localization of TG2 in cells derived from and NZB╱W F1 mice. Mice were divided into two groups and various tissue samples including macrophage, heart, liver, spleen, lung, kidney and muscle were collected at age of 6 week and 24 week. The localization and expression of TG2 were determined by RT-PCR and immunoblotting. The phagocytic ability of macrophage was also examined and compared among Balb╱C and NZB╱W F1 mice at age of 6 and 24 week. Since the expression of TG2 protein in various organs from NNB╱W F1 mice, there is no expression variation between mice at age of 6 week and 24 week. Transglutaminase 2 (TG2), an inducible transamidating acyltransferase that catalyzes calcium-dependent protein modification, is involved in the pathogenesis of SLE. In the second year, we designed to examine whether the known association of TG2 with apoptosis and apoptotic clearance might explain its role in SLE. Our experimental results demonstrated that decreased phagocytic ability in macrophages of NZB╱W mice was not associated with changes in expression of TG2 (mRNA or protein), but was associated with increased TG2 activity. In the third year, we further identified the decreased phagocytic ability of macrophages from NZB╱W F1 mice. Experimental results demonstrated that increased caspase activity, and increased expression of Bax and Apaf-1 was associated with the reduced uptake of apoptotic bodies. This finding may account for the decreased phagocytic ability of macrophages in SLE mice.
URI:	https://ir.csmu.edu.tw:8080/handle/310902500/2846
Appears in Collections:	[醫學系] 研究計劃

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