本文選題：甲狀腺相關(guān)性眼病 + 細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)抑制分子-3　； 參考：《華中科技大學(xué)》2015年博士論文

【摘要】：研究背景和目的： 甲狀腺相關(guān)性眼病是與Graves病密切相關(guān)的眼眶組織炎癥,發(fā)病率居成年人眼眶疾病之首,大量細(xì)胞因子參與疾病過(guò)程,引起組織重構(gòu),但確切的發(fā)病機(jī)制尚不清楚。細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)抑制分子-3(suppressor of cytokine signaling-3, SOCS3)作為細(xì)胞因子重要的負(fù)調(diào)控因子,在多種炎癥性疾病發(fā)生、發(fā)展過(guò)程中起到重要的作用。本研究探討SOCS3蛋白與甲狀腺相關(guān)性眼病的關(guān)系。 方法： 1.取甲狀腺相關(guān)性眼病患者和正常人的眶脂肪組織,檢測(cè)眶脂肪組織中是否表達(dá)SOCS3蛋白。使用免疫熒光法。 2.分別由甲狀腺相關(guān)性眼病患者和正常人眼眶結(jié)締組織分離培養(yǎng)成纖維細(xì)胞,檢測(cè)兩組眼眶成纖維細(xì)胞中SOCS3mRNA和蛋白質(zhì)的表達(dá)差異。使用real-time PCR和Western blot法。 3.收集270例Graves病患者病例資料及外周靜脈血。將所有患者根據(jù)有無(wú)眼病分為Graves病伴有眼病組(114例)和Graves病不伴眼病組(156例)。分別取兩組患者外周血單核細(xì)胞(PBMC),建立EB病毒轉(zhuǎn)化的類(lèi)淋巴母細(xì)胞系(Epstein-Barr virus lymphoblastoid cell lines, EBV-LCLs)。檢測(cè)兩組患者EBV-LCLs中SOCS3mRNA和蛋白質(zhì)的表達(dá)差異。使用real-time PCR和Western blot方法。對(duì)所有患者SOCS3基因5個(gè)位點(diǎn)(rs12952093, rs4969170, rs4969168, rs4969169and rs2280148)進(jìn)行測(cè)序分型,采用連接酶檢測(cè)反應(yīng)-PCR (LDR-PCR)基因測(cè)序分型技術(shù)。多因素Logistic回歸分析SOCS3基因各位點(diǎn)基因型與甲狀腺相關(guān)性眼病間的關(guān)系。為進(jìn)一步驗(yàn)證與眼病有關(guān)的基因型是否影響基因功能,研究繼續(xù)觀(guān)察該基因型是否影響SOCS3表達(dá)。使用real-time PCR和Western blot法。 結(jié)果： 1.甲狀腺相關(guān)性眼病患者眶脂肪組織表達(dá)SOCS3蛋白非常明顯,正常人組織中微量表達(dá)。 2.甲狀腺相關(guān)性眼病患者眶成纖維細(xì)胞中SOCS3mRNA和蛋白質(zhì)的水平較正常人顯著增高(p0.05)。 3. Graves病伴眼病患者EBV-LCLs中SOCS3mRNA和蛋白的表達(dá)水平較Graves病無(wú)眼病患者顯著增高(p0.05)。 4.校正年齡、性別、BMI,吸煙,甲狀腺腫,甲狀腺結(jié)節(jié),黏液性水腫,Graves病治療(藥物,放射性治療,甲狀腺切除術(shù))以及高血壓這些因素后,經(jīng)多因素Logistic回歸分析,SOCS3rs4969170AA基因型與甲狀腺相關(guān)性眼病風(fēng)險(xiǎn)增高有關(guān)(OR-3.5,95%CI1.6to7.5, p=0.001).而SOCS3rs12952093, rs4969168,rs4969169及rs2280148與甲狀腺相關(guān)性眼病的關(guān)聯(lián)均沒(méi)有達(dá)到統(tǒng)計(jì)學(xué)顯著性水平。SOCS3rs4969170AA基因型甲狀腺相關(guān)性眼病患者EBV-LCLs中SOCS3mRNA和蛋白表達(dá)水平較GG型眼病患者顯著增高。 結(jié)論： SOCS3蛋白與甲狀腺相關(guān)性眼病有關(guān)。甲狀腺相關(guān)性眼病患者中SOCS3rs4969170可能是功能性單核苷酸多態(tài)性(Single nucleotide polymorphism, SNP),該位點(diǎn)AA基因型可能通過(guò)增加SOCS3表達(dá),與甲狀腺相關(guān)性眼病風(fēng)險(xiǎn)增加有關(guān)。
[Abstract]:Background and objectives of the study: Thyroid associated ophthalmopathy is a kind of orbital inflammation closely related to Graves's disease. The incidence rate is the highest among adult orbital diseases. A large number of cytokines participate in the process of the disease and cause tissue remodeling, but the exact pathogenesis is not clear. Cytokine signal transduction suppressor of cytokine signaling-3 (SOCS3), as an important negative regulator of cytokines, plays an important role in the occurrence and development of various inflammatory diseases. This study was to investigate the relationship between SOCS3 protein and thyroid associated ophthalmopathy. Methods: 1. The orbital adipose tissues of patients with thyroid associated ophthalmopathy and normal subjects were taken to detect the expression of SOCS3 protein in orbital adipose tissue. Immunofluorescence method was used. 2. The fibroblasts were isolated from the orbital connective tissue of the patients with thyroid associated ophthalmopathy and the normal subjects. The expression of SOCS3mRNA and protein in the orbital fibroblasts of the two groups were detected. Real-time PCR and Western blot methods were used. 3. Data of 270 patients with Graves's disease and peripheral venous blood were collected. All the patients were divided into two groups according to the presence or absence of ophthalmopathy: Graves's disease with ophthalmopathy (n = 114) and Graves's disease without ophthalmopathy (n = 156). Epstein-Barr virus lymphoblastoid cell lines, EBV-LCLs were isolated from peripheral blood monocytes of two groups of patients and transformed into Epstein-Barr virus lymphoblastoid cell lines, EBV-LCLs1 cell lines. The expression of SOCS3mRNA and protein in EBV-LCLs of the two groups were detected. Use real-time PCR and Western blot methods. Five loci of SOCS3 gene (rs12952093, rs4969170, rs4969168, rs4969169and rs2280148) were sequenced. Multivariate Logistic regression analysis showed the relationship between SOCS3 gene genotypes and thyroid associated ophthalmopathy. To further verify whether the gene function was affected by the genotype associated with eye disease, the study continued to observe whether the genotype affected the expression of SOCS3. Real-time PCR and Western blot methods were used. Results: 1. The expression of SOCS3 protein in orbital adipose tissue of thyroid associated ophthalmopathy patients was very obvious, and the expression of SOCS3 protein in normal tissue was very small. 2. The levels of SOCS3mRNA and protein in orbital fibroblasts in patients with thyroid associated ophthalmopathy were significantly higher than those in normal controls (P 0.05). 3. The expression of SOCS3mRNA and protein in EBV-LCLs in patients with Graves disease and ophthalmopathy was significantly higher than that in patients without Graves disease. 4. Adjusted for age, sex, BMI, smoking, goiter, thyroid nodule, mucinous edema, Graves' disease treatment (drugs, radiation therapy, thyroidectomy) and hypertension. Multivariate Logistic regression analysis showed that SOCS3rs4969170AA genotype was associated with increased risk of thyroid associated ophthalmopathy. The correlation between SOCS3rs12952093, rs4969168rs4969169 and rs2280148 was not statistically significant. The expression of SOCS3mRNA and protein in EBV-LCLs of patients with thyroid associated ophthalmopathy genotype SOCS3rs4969170AA was significantly higher than that of patients with GG type ophthalmopathy. Conclusion: SOCS3 protein is associated with thyroid associated ophthalmopathy. SOCS3rs4969170 may be a functional single nucleotide polymorphism (SNPs) in patients with thyroid associated ophthalmopathy. The AA genotype at this locus may be associated with an increased risk of thyroid associated ophthalmopathy by increasing the expression of SOCS3.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R777.5

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