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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18924完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 賴向華(Eddie Hsiang-Hua Lai) | |
| dc.contributor.author | Hsuan-Fang Wang | en |
| dc.contributor.author | 王宣方 | zh_TW |
| dc.date.accessioned | 2021-06-08T01:39:46Z | - |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-22 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18924 | - |
| dc.description.abstract | 類風濕性關節炎 (rheumatoid arthritis) 是一種多因性的自體免疫疾病，盛行率約佔世界人口的1%，主要特徵為滑膜關節 (synovial joint) 的慢性發炎，若不介入適當治療，會逐漸演變為關節的破壞與失能。臨床上約有4%至80%的類風濕性關節炎患者顳顎關節也有受到類風濕性關節炎的侵犯，除了關節壓痛 (tenderness)、疼痛 (pain)、腫脹、關節彈響聲 (clicking)或捻髮聲 (crepitation)、晨僵 (morning stiffness)、下顎活動與張口受限、咬力減弱等症狀外；隨著疾病的進展，較嚴重的案例會出現下顎髁頭 (condylar head) 與關節隆突 (articular eminence) 的吸收與破壞，除了造成關節不適與功能限制外，也會逐漸發展成前牙開咬與下顎後縮的不正咬合。
目前類風濕性關節炎患者主要使用的治療藥物包括非類固醇抗發炎藥、疾病修飾抗風濕病藥 (disease modifying anti-rheumatic drugs，DMARDs) 以及生物製劑等；雖然生物製劑如抗細胞激素療法 (cytokine antagonist)、B細胞消除療法 (B cell deletion) 及抗T細胞療法等大大提高臨床上的治療效果，但都只能對部分患者有效，無法提供全面性的治療效果。目前已知滑膜纖維母細胞在類風濕性關節炎的致病機轉中扮演了關鍵的角色，滑膜纖維母細胞的大量增生造成慢性持續的發炎反應以及關節的破壞，若能找到抑制它的療法，不但可減少關節的破壞、緩解因滑膜纖維母細胞所引起的一連串發炎反應，也可讓藥物的作用更針對目標組織，減少對整體免疫系統的影響。 在慢性發炎的缺氧環境中，代謝重整對滑膜纖維母細胞的增生扮演了重要的角色，本實驗的研究結果顯示類風濕性關節炎中的缺氧環境，會使glutaminase的表現量與活性增加，造成glutaminase的下游產物glutamate產量上升，促使滑膜纖維母細胞分泌CCL20，造成發炎反應的持續進行與關節的破壞。而SIRT5能抑制缺氧刺激下所增加的glutaminase表現量與活性，減少缺氧刺激對glutaminolysis這條路徑的活化以及缺氧刺激所誘發的CCL20分泌，進而減緩類風濕性關節炎的進展，期許本機制的研究能為類風濕性關節炎的治療提供一個有潛力的新途徑。 | zh_TW |
| dc.description.abstract | Rheumatoid arthritis (RA) is a multifactorial autoimmune disease affecting 1% of the world population. The pathology is characterized by chronic inflammation of synovial joints, leading to joint destruction and disability. 4% to 80% RA patients exhibit clinical temporomandibular joints (TMJ) involvement. The clinical findings in TMJ affected by RA include joint and muscle tenderness, pain, swelling, clicking sound, crepitation, morning stiffness, restricted mandibular movement, mouth open limitation, and reduced bite forces. As the progression of the disease, bone resorption may exacerbate joint dysfunction and develop malocclusion such as anterior open bite and mandibular retrognathism.
The current treatments of RA include nonsteroidal anti-inflammatory drug (NSAID), disease modifying anti-rheumatic drugs (DMARDs), and biological therapies. The introduction of biological therapies such as cytokine antagonist, B cell depletion, and T cell co-stimulation blockers markedly improved clinical outcomes but just in part of selected patients. Rheumatoid arthritis synovial fibroblasts (RASFs) play a key role in rheumatoid arthritis with its dramatic increase in number and aggressive behavior, contributing to persistent inflammation and destruction of joint. Targeting RASFs might improve clinical outcomes in persistent joint inflammation and bone destruction without suppressing systemic immunity. In the hypoxic environment of the inflamed joint, metabolic reprogramming plays an important role in the survival and overgrowth of RASFs. Our data have demonstrated the hypoxic environment of rheumatoid arthritis may increase the amount and activity of glutaminase, contributing to the increase of the product of glutaminolysis, glutamate. The elevated amount of glutamate may further stimulate CCL20 production by RASFs and lead to the progression of RA. SIRT5 may attenuate the progression of RA via modulating hypoxia-induced glutaminolysis reprogramming and CCL20 secretion in RASFs. This finding may provide a therapeutic potential of RA. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T01:39:46Z (GMT). No. of bitstreams: 1 ntu-105-R02422017-1.pdf: 1775459 bytes, checksum: 36814bfe7ed3d07af1aa58291b1baaab (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 口試委員審定書 i
誌謝 ii 中文摘要 iii Abstract v 目錄 vii 第一章 導論 1 1.1 類風濕性關節炎 (rheumatoid arthritis，RA) 1 1.2 滑膜纖維母細胞在類風濕性關節炎中所扮演的角色 2 1.3 CC趨化因子20與類風濕性關節炎 4 1.4 受類風濕性關節炎侵犯關節中的缺氧環境 5 1.5 代謝重整 (metabolism reprogramming) 6 1.5.1 糖解作用 (glycolysis) 與氧化磷酸化 (oxidative phosphorylation, OxPhos) 6 1.5.2 穀氨醯胺分解 (glutaminolysis) 7 1.5.3 穀氨醯胺酶 (Glutaminase, GLS) 7 1.6 SIRT5與類風濕性關節炎進展的可能關聯性 9 第二章 實驗目的 11 第三章 材料與方法 13 3.1 試劑與抗體 13 3.2 實驗細胞株 13 3.3 建立SIRT5穩定表達細胞株 (SIRT5 stable cell line) 13 3.4 細胞缺氧刺激 14 3.5 細胞粒腺體內GLS蛋白質的萃取 14 3.6 西方點墨法 (Western blot) 15 3.7 檢測glutaminase活性: glutaminase activity assay 16 3.8 酵素免疫分析法: CCL20 ELISA assay 17 3.9 免疫共沉澱法 (Co-Immunoprecipitation, Co-IP) 17 3.10 GLS蛋白succinylation修飾偵測 17 第四章 實驗結果 19 4.1 SIRT5抑制缺氧刺激下所增加的GLS 蛋白質表現量 19 4.2 SIRT5抑制缺氧刺激下所增加的GLS 蛋白質活性 20 4.3 SIRT5在缺氧刺激下對GLS lysine succinylation的影響 21 4.4 SIRT5抑制缺氧刺激下所增加的CCL20分泌量 23 4.5 Glutamate恢復SIRT5所抑制的缺氧刺激下增加的CCL20分泌量 24 第五章 討論 27 5.1 SIRT5 在GLS lysine succinylation上所扮演的角色 27 5.2 滑膜纖維母細胞的代謝重整在類風濕性關節炎中所扮演的角色 28 第六章 結論 32 第七章 未來研究方向 33 參考文獻 35 附錄 43 | |
| dc.language.iso | zh-TW | |
| dc.title | SIRT5可經由調控缺氧所誘發之glutaminolysis代謝重整來減緩類風濕性關節炎的進展 | zh_TW |
| dc.title | SIRT5 Modulates Hypoxia-induced Glutaminolysis Reprogramming: Therapeutic Potential of Rheumatoid Arthritis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林思洸(Sze-Kwan Lin),洪志遠(Chi-Yuan Hong) | |
| dc.subject.keyword | 類風濕性關節炎,缺氧,滑膜纖維母細胞,代謝重整,glutaminolysis,SIRT5,CCL20, | zh_TW |
| dc.subject.keyword | rheumatoid arthritis,hypoxia,rheumatoid arthritis synovial fibroblast ( RASF),metabolic reprogramming,glutaminolysis,SIRT5,CCL20, | en |
| dc.relation.page | 60 | |
| dc.identifier.doi | 10.6342/NTU201603422 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2016-08-22 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 臨床牙醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床牙醫學研究所 | |
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