| Abstract: | Transglutaminase 2 (TG2)具多功能之酵素.把 c57BL/6 老鼠之 TG2 knockout 後.老鼠會變成 狼瘡樣疾病如脾臟腫大.清除凋亡細胞能力下降.產生多種自體抗體及腎絲球腎炎等症狀, 過去我們集中研究 TG2與細胞凋亡之關係.最近我們新發現 TG2可 cross-linking RAP1GDS1 調控細胞內鈣離子之平衡 (Transglutaminase 2 contributes to apoptosis induction in Jurkat T cells by modulating Ca2+ homeotasis via cross-linking RAP1GDS1, PLOS ONE 8(12):e81516,2013), TG2 可使 ER 之鈣離子進入 mitochondria 而引起細胞凋亡,這個發現 除了解細胞凋亡與字體免疫疾病之發生關係外,更進一步了解細胞內鈣離子之流動.顯示 TG2 具有參與各種疾病發生之機轉, 而 intracellular calcium homeostsis 參與 Th17 之 differentiation, 人體或動物無法清除凋亡細胞或清除凋亡細胞障礙 (defective efferocytosis or clearance of apoptotic cells)是人體或動物嚴重之缺失並可導致疾病產生. 無法清除凋亡細胞除在全身性紅斑性狼瘡(Systemic Lupus Erythematosus, SLE)參與重要 之機轉外,在糖尿病與慢性肺阻塞症 (COPD),與急動脈硬化也參與角色. 我們計劃研究這些現象與臨床疾病之關係. 本計劃將為三年計畫: 第一年研究 RAP1GDS1 與疾病之關係:以 RAP1GDS1 之 shRNA 研究細胞 cytokines, apoptosis 及 proliferation, 及研究各種自體免疫疾病病人之 GDS1 抗體 第二年研究清除凋亡之細胞 (efferocytosis) 與 AHR及 TG2之關係: we like to know what the role of AHR in efferocytosis and its relationship with TG2 and whether AHR will influences efferocytosis and TG2 or not. .第三年研究單鈉尿酸鹽結晶與 TG2 之訊息傳遞與關係.我們研究發現在痛風病人關節液 和滑膜中受 MSU 刺激之 RAW264.7 細胞株皆發現 TG2 增加.
Tissue or type 2 transglutaminase (TG2, EC 2.3.2.13) has been implicated in multiple disease states and is a multifunctional enzyme belonging to the transglutaminase family. The TG2 knockout c57BL/6 mice will develop lupus-like disease including splenomegaly, defective clearance of apoptotic cells or efferocytosis, production of autoantibodies and glomerulonephritis. Recently we found TG2 might contribute to apoptosis by acting as a Ca2+ sensor in the mitochondria to amplify ER-Derived Ca2+ signal via cross-linking RAP1GDS1(PLOS ONE 8(12):e81516,2013). We also found that Retinoids produced by macrophages engulfing apoptotic cells contribute to the appearance of TG2 in apoptotic thymocytes (Amino Acids. 2011 oct.14).These results indicated a more general role of TG2 in the regulation of Calcium homeostasis and T17 cell differentiation, efferocytosis and the pathogenesis in autoimmune diseases. The defective efferocytosis is the key mechanism for the pathogenesis of lupus and other diseases such as diabetes and chronic obstructive pulmonary disease (COPD). We will further to study the role of TG2 and RAP1GDS1 in inflammation process and cytokine production and the regulation of calcium in Th17 differentiation. Since it has been reported that the association of Arylhydrocarbon receptor (AHR) and the pathogenesis of diseases, including Rheumatoid arthritis (RA) and lung cancer, we will investigate the relationship between AHR, TG2 and RAP1GDS1 in autoimmune disease and other arthritis such as gout and osteoarthritis (OA). The study will be done in a three-year period: 1. The first year: to study the role of RAP1GDS1 shRNA in cytokine production, apoptosis and cell proliferation and to screen anti-RAP1GDS1 antibody in patients with autoimmune diseases. 2. The second year: to study the relationship among efferocytosis and AHR and TG2 3. The third year: to study the relationship between TG2 and monosodium urate (MSU). We have found that TG2 increased in synovial membrane of patients with gout and in the RAW264.7 cell after stimulation with MSU. |
