2026-11-092026-11-09https://scholars.csmu.edu.tw/handle/123456789/38573Rheumatoid arthritis (RA) is a common autoimmune disease that affects about 1% of the population in the world and causes huge loss of the countries and burden of the economy. Among the autoantibodies in the patients with RA, anti–citrullinated protein antibodies (ACPAs) are highly specific and have thus become part of the diagnostic tool in inflammatory arthritis. Circumstantial clinical evidence also suggests that ACPAs may participate in important pathophysiologic processes in RA. It becomes increasingly clear that well-defined citrullinated epitopes, rather than the mere presence of citrullinated proteins as such, may be relevant for the induction of ACPAs and, eventually, for the pathogenicity of anticitrulline reactivity. Therefore, searching the new clinically relevant citrullinated epitopes and experimentally assessing the requirements for optimal and coordinated immune activation by these epitopes are two major challenges in this field. The key enzymes that contribute the citrullinated proteins as the autoantigens of RA are peptidylarginine deiminases (PADIs). Two members of PADI family, PADI2 and PADI4, are reported to be expressed in synovial tissues and associated with RA. PADIs are specifically activated during the apoptosis. In our previous studies, PADI2 and PADI4 induced apoptosis. Besides apoptosis, PADI4 with the character of nuclear localization has come into focus as a novel posttranslational modification of histones linked to gene regulation. Here, we further dig the functions of PADI2 and PAID4 in the different aspects to the gene regulation, apoptosis and pathogenesis of RA, as the specific aims shown below. Aim 1: Investigate the Effects of PADI4 on Regulating Gene Expression Aim 2: Explore the Apoptotic Mechanisms of PADI2 and PADI4 Aim 3: Explore the Way of Presenting Citrullinated Proteins to the Immune Systems Aim 4: Search New Citrullinated Proteins Extracted from the Cells Overexpressing PADI2 or PADI4 Aim 5: Investigate the Epitopes of New Citrullinated Autoantigen of Rheumatoid Arthritis類風濕性關節炎是一個常見的自體免疫疾病，侵犯全球約百分之ㄧ的人口，造成社 會巨大的損失及經濟的負擔。在類風濕性關節炎病患血清中出現的自體免疫抗體中，抗 瓜胺酸化蛋白質抗體具有高度的專一性，也因此成為發炎性關節炎的診斷利器。間接臨 床的證據顯示抗瓜胺酸化蛋白質抗體可能參與類風濕性關節炎的致病機轉。愈來愈清楚 的是含瓜胺酸的抗原決定位點(citrullinated epitopes)，而非整個蛋白質，為引發抗瓜胺酸 化蛋白質抗體產生的重要依據。因此尋找新的含瓜胺酸的抗原決定位點以及這些含瓜胺 酸的抗原決定位點如何引發免疫反應，為現今兩個主要的問題。 而形成瓜胺酸化蛋白質的主要酵素為勝.精胺酸脫亞氨.。勝.精胺酸脫亞氨.家 族中的兩個成員，第二及第四型勝.精胺酸脫亞氨.，被發現存在於發炎滑囊膜中，並 與類風濕性關節炎有關。已知勝.精胺酸脫亞氨.活性特別在細胞凋亡的過程中表現出 來。在我們先前的研究中顯示過度表現這兩種酵素都會造成細胞凋亡。除了細胞凋亡之 外，第四型勝.精胺酸脫亞氨.具有轉移至細胞核中的特色，而成為一種新的可藉由轉 譯後修飾的方式來調控基因的表現的焦點。 在此，我們將進一步深入探討第二及第四型勝.精胺酸脫亞氨.的相關功能，包括 基因調控、細胞凋亡及類風溼性關節炎的致病機轉等方面，條列於下： 主題一: 研究第四型勝.精胺酸脫亞氨.在調節基因表現的作用 主題二: 探索第二及第四型勝.精胺酸脫亞氨.造成細胞凋亡的機制 主題三: 探索將瓜胺酸化蛋白質呈現給免疫系統成為自體免疫抗原的方式 主題四: 從過度表現第二或第四型勝.精胺酸脫亞氨.細胞中找尋新的瓜胺酸化蛋白質 主題五: 研究與類風濕性關節炎有關的瓜胺酸化自體免疫抗原上的抗原決定位點胜精胺酸脫亞氨細胞凋亡脫亞氨反應抗原決定位peptidylarginine deiminasesapoptosisdeiminationepitopeProject