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論文名稱 Title |
糖尿病人原始免疫反應異常之研究 Alteration of Innate Immune Reaction in Patients with Type 2 Diabetes Mellitus |
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系所名稱 Department |
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畢業學年期 Year, semester |
語文別 Language |
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學位類別 Degree |
頁數 Number of pages |
45 |
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研究生 Author |
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指導教授 Advisor |
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召集委員 Convenor |
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口試委員 Advisory Committee |
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口試日期 Date of Exam |
2006-05-17 |
繳交日期 Date of Submission |
2006-06-22 |
關鍵字 Keywords |
氧化自由基、糖尿病 SOCS-1, TLR-4, TNF-α |
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統計 Statistics |
本論文已被瀏覽 5696 次,被下載 3305 次 The thesis/dissertation has been browsed 5696 times, has been downloaded 3305 times. |
中文摘要 |
糖尿病在台灣十大死亡病因中排名第四位。越來越多證據顯 示,糖尿病的心血管併發症與慢性免疫炎症有關。然而糖尿病所引 發的慢性炎症機制尚不清楚。我們因此針對糖尿病人免疫功能的議 題進行探討,藉由研究正常人和糖尿病人的白血球原始免疫力中路 橋分子(Toll-like receptors;TLRs)的表現與活化的不同,探討糖尿 病人原始免疫的異常。因此,我們總共選用31 個第2 型糖尿病人及 37 個年齡配對的正常人檢體中,針對TLR-2 和TLR-4 的表現與白 血球訊息傳遞進行研究。實驗是以每次取一至二位糖尿病人白血 球,以及一至二位同年齡正常人白血球為對照組來進行。結果發現 糖尿病人全血中的單核球細胞TLR-2 表現正常,但是TLR-4 的表現 有明顯比正常人增加。可見糖尿病人的原始免疫表現有著異常反 應,這可能與其異常慢性發炎有關。所以我們進一步將正常人和糖 尿病人的白血球和TLR-4 配體(細菌脂多醣類;LPS)進行培養6 小 時,偵測細胞激素TNF-α及IL-8 表現。同時也比較抑制細胞素訊息 (SOCS-1, SOCS-3) mRNA 表現。實驗當中發現糖尿病人白血球 TNF-α產生量比正常人高(p=0.033)。相對地,糖尿病人在LPS 作用 下SOCS-1( p=0.001)和SOCS-3(p=0.011)表現皆有負調控現象。進一 步假設糖尿病人是由於氧化自由基過多或干擾素產生減少,而造成 免疫細胞調控失常而導致發炎增加。我們使用抗氧化劑和外加干擾 素IFN-α去調整SOCS-1 的表現。結果發現抗氧化劑可以增加 SOCS-1 的表現和降低細胞激素TNF-α的產生;而外加IFN-α可以恢 復SOCS-1 的表現,但不會抑制TNF-α的產生。這個研究首先證實 糖尿病人全血中的單核球TLR-4 表現和訊息傳遞異常,而造成炎症 物質TNF-α增加。這些研究結果將有助於人們透過調節TLR-4 和 SOCS-1 表現來減少糖尿病人白血球的慢性炎症反應。 |
Abstract |
Diabetes mellitus (DM) is the 4th leading cause of mortality in Taiwan. Chronic persistent inflammation as demonstrated by higher proinflammatory mediators in blood has been correlated to cardiovascular complications of type 2 DM. The cellular and molecular mechanism of chronic inflammation in type 2 DM remains to be determined. This study was conducted to explore altered innate immunity in toll-like receptor (TLR) expression and signaling of monocytes from type 2 DM patients. Blood leukocytes from type 2 DM patients were counted and studied for TLR2 and TLR4 expression and signaling. Each experiment was run with 1 to 2 type 2 DM patients, simultaneously with 1 to 2 age-matched normal adults as controls. 31 type 2 DM patients and 37 normal age-matched controls completed the study. Results showed that blood monocytes from type 2 DM patients had a significantly higher TLR4 but not TLR2 expression. Using a TLR4 ligand, lipopolysaccharide (LPS), to trigger TNFα production, a significantly higher TNFα production by blood leukocytes from type 2 DM patients than age-matched controls was found. The higher TNFα production by blood leukocytes from type 2 DM patients was associated with down-regulation of suppressor of cytokine signaling 1and 3 (SOCS-1 and SOCS-3) expression. We have further postulated that increase of oxidative stress or decrease of IFN-α production in type 2 DM patients was related to the alteration of TLR-4 response. Correction of SOCS-1 expression by addition of antioxidant, superoxide dismutase (SOD), but not IFN-α, significantly decreased TNFα production in blood leukocytes from type 2 DM patients. This study is the first in the literature to identify an alteration of TLR4 expression associated with depressed SOCS-1 expression in leukocytes of type 2 DM patients. Results from this study highlight a potential pathway to improve chronic inflammation of type 2 DM patients via modulation of TLR4 expression and SOCS-1 mRNA expression of leukocytes. |
目次 Table of Contents |
目錄………………………………………………………………………1 壹、中文摘要……………………………………………………………2 貳、英文摘要……………………………………………………………3 參、前言…………………………………………………………………4 肆、研究目的……………………………………………………………9 伍、實驗材料和方法………………………………………………… 10 陸、結果……………………………………………………………… 17 柒、討論……………………………………………………………… 20 捌、參考文獻………………………………………………………… 23 玖、圖表……………………………………………………………… 29 |
參考文獻 References |
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