本文選題：類風(fēng)濕關(guān)節(jié)炎 + TXNDC5　； 參考：《山東大學(xué)》2017年碩士論文

【摘要】：研究背景:類風(fēng)濕關(guān)節(jié)炎(rheumatoid arthritis,RA)患病率為0.35%,是一種慢性系統(tǒng)性自身免疫性疾病,主要臨床表現(xiàn)為關(guān)節(jié)損傷和滑膜炎癥,組織病理學(xué)特征為關(guān)節(jié)滑膜細(xì)胞增殖、細(xì)胞浸潤能力增強(qiáng)、細(xì)胞凋亡降低、血管翳形成和大量炎性細(xì)胞浸潤。RA導(dǎo)致患者關(guān)節(jié)活動(dòng)明顯受限甚至致軀體殘疾,嚴(yán)重威脅著人類的健康。但是該病的致病機(jī)制尚不完全明確,治療藥物也僅以抗炎藥物為主。因此,RA開展相關(guān)的細(xì)胞和分子機(jī)制的研究對RA的診治具有重要意義。硫氧還蛋白 5(thioredoxin domain containing protein 5,TXNDC5)基因編碼的蛋白質(zhì)屬于蛋白質(zhì)二硫鍵異構(gòu)酶家族,可催化二硫鍵的重排,具有抗氧化、促進(jìn)血管形成,參與細(xì)胞炎癥等多種生物功能。我們的前期研究發(fā)現(xiàn),TXNDC5在RA患者的滑膜組織和血液中高表達(dá),其編碼基因是RA的遺傳易感基因。我們的實(shí)驗(yàn)動(dòng)物學(xué)研究證明,TXNDC5轉(zhuǎn)基因小鼠更易于被膠原Ⅱ誘導(dǎo)出關(guān)節(jié)炎。因此我們建議,TXNDC5在RA發(fā)病過程中發(fā)揮重要作用,雖然其具體致病機(jī)制尚不清楚。本課題研究的目的就是探索TXNDC5如何參與、影響RA的病變過程。近年的基因組學(xué)及其他分子生物學(xué)研究顯示,TXNDC5是糖尿病易感基因,在糖尿病發(fā)病過程中發(fā)揮重要作用。糖尿病是一種由于胰島素分泌缺陷或胰島素作用障礙所致的以高血糖為特征的代謝性疾病,常伴有胰島素抵抗或胰島素相關(guān)信號通路的異常。其他人的研究證明,TXNDC5不僅能催化胰島素二硫鍵的還原,減少胰島素的合成,而且可以降低胰島素與其受體的結(jié)合活性,加劇糖尿病病情。流行病學(xué)調(diào)查也顯示,RA患者中2型糖尿病的患病風(fēng)險(xiǎn)增高,患者機(jī)體胰島素抵抗增強(qiáng)。另外,大量研究提示,RA的炎癥活動(dòng)及炎癥介質(zhì)影響糖代謝、胰島素信號通路及胰島素抵抗相關(guān)通路,進(jìn)而提高了 RA患者罹患糖尿病的風(fēng)險(xiǎn)。鑒于RA與糖尿病患病風(fēng)險(xiǎn)的關(guān)系以及TXNDC5在兩種疾病中的重要作用,提示我們TXNDC5有可能通過胰島素相關(guān)信號通路參與RA的發(fā)生發(fā)展。因此,本課題計(jì)劃探索TXNDC5是否通過胰島素信號途徑參與RA病變過程,分析TXNDC5與胰島素抵抗、胰島素信號通路相關(guān)基因之間的關(guān)系。本課題也計(jì)劃在分子水平上了解RA與糖尿病之間的內(nèi)在聯(lián)系。目的:類風(fēng)濕關(guān)節(jié)炎滑膜細(xì)胞(rheumatoid arthritis synovial cells,RASFs)是 RA關(guān)節(jié)滑膜中的重要組成成分,有顯著增強(qiáng)的增殖能力,可分泌多種炎癥因子和生長因子,促進(jìn)RA滑膜炎和關(guān)節(jié)組織破壞過程。為了研究TXNDC5對RA的致病機(jī)制和作用,本課題首先用小分子RNA抑制RASFs中TXNDC5的表達(dá),然后觀察細(xì)胞的增殖、遷移和凋亡變化情況。同時(shí),用PCRarray分析anti-TXNDC5 siRNA處理的RASFs,篩選TXNDC5在RASFs中參與胰島素抵抗或者胰島素信號通路的相關(guān)基因,然后用Real-time PCR、ELISA、Western blot等方法驗(yàn)證PCR array結(jié)果。PCRarray是近幾年興起的快速篩選信號途徑和疾病關(guān)聯(lián)基因的技術(shù)。該技術(shù)把一信號途徑或一疾病所用相關(guān)基因裝載在一芯片上,通過Real-time PCR技術(shù)一次性篩選到目的基因。方法:采用瞬時(shí)轉(zhuǎn)染的方法將針對TXNDC5小干擾RNA(siRNA)導(dǎo)入在RASFs中,抑制TXNDC5的表達(dá),然后采用Real-time PCR和Western blot技術(shù)檢測TXNDC5的mRNA和蛋白表達(dá)水平;采用CCK8增殖實(shí)驗(yàn)、細(xì)胞遷移實(shí)驗(yàn)以及流式細(xì)胞術(shù)分別檢測抗TXNDC5 siRNA處理組(anti-TXNDC5 siRNA組)RASFs的增殖、遷移和凋亡,對照組包括空白對照組、陰性對照組(AllstarsiRNA處理組);采用 insulin resistance RT2 Profiler PCR Array 和 insulin signaling pathway RT2 Profiler PCR Array 分別分析 anti-TXNDC5 siRNA 轉(zhuǎn)染的 RASFs 和 Allstar siRNA轉(zhuǎn)染的RASFs,通過比較相關(guān)基因的差異表達(dá)發(fā)現(xiàn)TXNDC5的下游調(diào)控基因;采用 Real-time PCR 和 ELISA 法驗(yàn)證 PCR array 結(jié)果;采用 Real-time PCR和Western blot檢測RA和骨關(guān)節(jié)炎(Osteoarthritis,OA)滑膜組織中IGFBP1(insulin like growth factor binding protein 1)的表達(dá)水平。結(jié)果:實(shí)驗(yàn)結(jié)果顯示,抑制TXNDC5的表達(dá)后,RASFs細(xì)胞的增殖(P=0.003)和遷移能力(P=0.002)明顯降低,凋亡明顯增加(P=0.006);PCRArray在anti-TXNDC5 siRNA組和Allstar siRNA組中共檢測到5個(gè)差異表達(dá)的基因,其中 insulin resistance RT2 Profiler PCR Array 篩選出 IGF-1(insulin like growth factor-1)、PCK1(phosphoenolpyruvate carboxykinase 1)、SLC2A4(solute carrier family 2 member 4)和 IL1Rl(interleukin 1 receptor type 1)基因,insulin signaling pathway RT2 Profiler PCR Array 篩選出 IGFBP1 基因。Real-time PCR 驗(yàn)證上述結(jié)果,證實(shí) IGFBP1 在 anti-TXNDC5 siRNA 組中顯著增高(P=0.005),而 IGF-1、PCK1、SLC2A4和IL1R1的表達(dá)在兩組間差異沒有統(tǒng)計(jì)學(xué)意義;ELISA證實(shí)IGFBP1的蛋白水平在anti-TXNDC5 siRNA轉(zhuǎn)染RASFs的細(xì)胞培養(yǎng)液中顯著增高(P0.001);由于有文獻(xiàn)報(bào)道 IGFBP3(insulin like growth factor binding protein 3)在RASFs中表達(dá),并在IGF信號途徑中發(fā)揮重要作用,而且IGFBP3與IGFBP1的功能十分相似,都是IGF-1重要的結(jié)合蛋白,我們也用Real-time PCR檢測IGFBP3的表達(dá)水平。結(jié)果顯示,IGFBP3的表達(dá)在兩組間沒有差異;Real-time PCR分析了人RA和OA組織中IGFBP1的表達(dá),結(jié)果顯示RA滑膜組織中IGFBP1的mRNA表達(dá)明顯低于OA滑膜組織(P=0.011)。同樣,Western blot結(jié)果顯示RA組織中IGFBP1的蛋白表達(dá)較OA組織中明顯降低(P=0.014)。實(shí)驗(yàn)結(jié)果顯示,抑制RASFs中TXNDC5的表達(dá)后,IGFBP1的表達(dá)量增高,而IGF-1和IGFBP3的表達(dá)并未發(fā)生變化。Western blot結(jié)果顯示相對于OA滑膜組織,RA滑膜組織中IGFBP1表達(dá)降低。結(jié)論:以上結(jié)果顯示,RASFs中TXNDC5被抑制后,IGFBP1的表達(dá)增加。我們前期工作已證明RA滑膜組織中高表達(dá)TXNDC5。因此,本研究結(jié)果建議,RASFs高表達(dá)TXNDC5可能會(huì)抑制IGFBP1的表達(dá)。由于IGFBP與IGF-1結(jié)合可以抑制IGF活性。因此,我們的結(jié)果還建議RA滑膜中高表達(dá)的TXNDC5通過抑制1GFBP1表達(dá)增加IGF-1/IGFBP1比值而提高IGF-1的活性。已有報(bào)道,IGF-1具有促炎和抑制細(xì)胞凋亡的作用,并且還能促進(jìn)多種細(xì)胞的增殖、分化及遷移。本研究發(fā)現(xiàn)抑制TXNDC5表達(dá)后,RASFs細(xì)胞增殖、遷移能力降低,凋亡率增加。這可能是由于增高的IGFBP1抑制了 IGF-1的活性致使細(xì)胞的行為發(fā)生改變�？傊�,結(jié)合以前的工作和本研究的結(jié)果,我們建議TXNDC5參與RA病變過程如下:TXNDC5在RA滑膜細(xì)胞中高表達(dá),通過抑制IGFBP1表達(dá)而不是IGFBP3刺激IGF-1活性,從而增強(qiáng)RASFs增殖、浸潤能力并抑制細(xì)胞凋亡,結(jié)果促進(jìn)RA的病程進(jìn)展。本研究在RA滑膜組織中發(fā)現(xiàn)IGFBP1低表達(dá)也證明了該建議。另外,有人也發(fā)現(xiàn)糖尿病患者血液中IGFBP1表達(dá)水平明顯異常、IGF-1活性明顯變化。本研究的結(jié)果也建議TXNDC5以及對IGFBP1表達(dá)的調(diào)控可能是RA與糖尿病之間內(nèi)在聯(lián)系的重要分子機(jī)制。TXNDC5負(fù)向調(diào)控IGFBP1表達(dá)以及影響RASFs細(xì)胞功能的發(fā)現(xiàn),為研究RA的發(fā)病機(jī)制提供了新的思路。
[Abstract]:Background: the prevalence of rheumatoid arthritis (RA) is 0.35%. It is a chronic systemic autoimmune disease. The main clinical manifestations are joint injury and synovial inflammation. Histopathological features are joint synovial cell proliferation, cell infiltration capacity, cell apoptosis, pannus formation and large number of inflammatory cells. Infiltration of.RA leads to significantly limited joint activity and even physical disability, which is a serious threat to human health. However, the pathogenesis of the disease is not completely clear, and the treatment drugs are mainly anti inflammatory drugs. Therefore, the study of RA related cellular and molecular mechanisms is of great significance to the diagnosis of RA. Thioredoxin 5 (thioredoxi N domain containing protein 5, TXNDC5) gene encoded proteins belong to the protein two sulfur bond isomerase family, which can catalyze the rearrangement of the two sulfur bond, have antioxidant activity, promote angiogenesis, and participate in many biological functions such as cell inflammation. Our previous study found that TXNDC5 was highly expressed in the synovial tissue and blood of RA patients and its coding base Our experimental zoological studies have shown that TXNDC5 transgenic mice are more prone to be induced by collagen II to induce arthritis. Therefore, we suggest that TXNDC5 play an important role in the pathogenesis of RA, although its specific pathogenesis is not clear. The purpose of this study is to explore how TXNDC5 participates in the effect of TXNDC5 and affects RA. The process of disease. In recent years, genomics and other molecular biology studies have shown that TXNDC5 is a susceptible gene for diabetes and plays an important role in the pathogenesis of diabetes. Diabetes is a metabolic disease characterized by hyperglycemia due to insulin secretion defect or insulin action disorder, often accompanied by insulin resistance or islets. Other people's studies have shown that TXNDC5 can not only catalyze the reduction of insulin two sulfur bonds, reduce insulin synthesis, but also reduce the binding activity of insulin to its receptors and aggravate the condition of diabetes. Epidemiological investigation also shows that the risk of type 2 diabetes is higher in patients with RA and the islets of the patients' body islets. In addition, a large number of studies have suggested that inflammatory activities and inflammatory mediators of RA affect glucose metabolism, insulin signaling pathways and insulin resistance related pathways, and thus enhance the risk of diabetes in RA patients. In view of the relationship between RA and the risk of diabetes and the important role of TXNDC5 in the two diseases, we suggest that we have TXNDC5 It is possible to participate in the development of RA through insulin signaling pathway. Therefore, we plan to explore whether TXNDC5 participates in the RA process through insulin signaling pathway, and analyzes the relationship between TXNDC5 and insulin resistance, and the relationship between insulin signaling pathway related genes. The subject also plans to understand the internal relationship between RA and diabetes at the molecular level. Objective: rheumatoid arthritis synovial cells (RASFs) is an important component of the synovial synovium of the RA joint. It has a significant enhancement of proliferation ability, can secrete a variety of inflammatory factors and growth factors, promote the process of RA synovitis and joint tissue destruction. In order to study the pathogenesis and effect of TXNDC5 to RA, the pathogenesis and effect of TXNDC5 are studied. Firstly, we use small molecule RNA to suppress the expression of TXNDC5 in RASFs, and then observe the proliferation, migration and apoptosis of cells. Meanwhile, we use PCRarray to analyze RASFs treated by anti-TXNDC5 siRNA and select the related genes involved in insulin resistance or insulin signaling pathway in RASFs, and then Real-time PCR, ELISA, and ELISA. OT and other methods verify the PCR array results.PCRarray is a rapid screening signal pathway and the technology of disease associated genes in recent years. The technology loaded a signal pathway or a disease related genes on a chip and screened the target gene by Real-time PCR technology. Method: the transient transfection method will be directed against TXND. C5 small interference RNA (siRNA) was introduced into RASFs to inhibit the expression of TXNDC5. Then Real-time PCR and Western blot techniques were used to detect mRNA and protein expression levels of TXNDC5. Proliferation, migration and apoptosis were detected by CCK8 proliferation, cell migration and flow cytometry, respectively. The control group, including the blank control group and the negative control group (AllstarsiRNA treatment group), used insulin resistance RT2 Profiler PCR Array and insulin signaling pathway RT2 Profiler. The downstream regulatory genes of DC5; Real-time PCR and ELISA methods were used to verify the PCR array results. Real-time PCR and Western blot were used to detect the expression level of RA and osteoarthritis (Osteoarthritis and osteoarthritis) synovial tissues. Cell proliferation (P=0.003) and migration ability (P=0.002) were significantly decreased, and apoptosis was significantly increased (P=0.006); PCRArray in anti-TXNDC5 siRNA group and Allstar siRNA group detected 5 differentially expressed genes, and insulin resistance RT2 Profiler. Carboxykinase 1), SLC2A4 (solute carrier family 2 member 4) and IL1Rl (interleukin 1 receptor type 1). The expression of IL1R1 was not statistically significant between the two groups; ELISA demonstrated that the protein level of IGFBP1 was significantly increased in the cell culture solution of anti-TXNDC5 siRNA transfected RASFs (P0.001), and that IGFBP3 (insulin like growth factor) was expressed in the anti-TXNDC5 siRNA and played an important role in the signaling pathway, The function of IGFBP3 and IGFBP1 is very similar, all of which are important binding proteins of IGF-1. We also use Real-time PCR to detect the expression level of IGFBP3. The results show that the expression of IGFBP3 is not different between the two groups; Real-time PCR analyses the expression of IGFBP1 in RA and OA tissues. Synovial tissue (P=0.011). Similarly, Western blot results showed that the expression of IGFBP1 protein in RA tissue was significantly lower than that in OA tissue (P=0.014). The results showed that the expression of IGFBP1 increased after inhibition of the expression of TXNDC5 in RASFs, while IGF-1 and IGFBP3 expression did not change, and the synovial membrane was shown to be relative to the synovial membrane. The expression of IGFBP1 in the tissue was reduced. Conclusion: the above results showed that the expression of IGFBP1 increased after the inhibition of TXNDC5 in RASFs. Our previous work has proved that the high expression of TXNDC5. in the RA synovial tissues has been proved. The results suggested that the high expression of TXNDC5 in RASFs may inhibit the expression of IGFBP1. The binding of IGFBP to IGF-1 can inhibit the activity of IGF. Therefore, the activity of IGFBP and IGF-1 can be suppressed. Our results also suggest that the high expression of TXNDC5 in the RA synovial membrane improves the activity of IGF-1 by inhibiting 1GFBP1 expression and increasing the IGF-1/IGFBP1 ratio. It has been reported that IGF-1 has the role of proinflammatory and inhibiting apoptosis, and also promotes the proliferation, differentiation and migration of multiple cells. This study found that the proliferation of RASFs cells was inhibited after the inhibition of TXNDC5 expression. Decrease in mobility and increase the rate of apoptosis. This may be due to the increased activity of IGFBP1 that inhibits the activity of IGF-1 causing changes in cell behavior. In conclusion, combined with previous work and the results of this study, we suggest that TXNDC5 participate in the process of RA lesions as follows: TXNDC5 is highly expressed in RA synovial cells by inhibiting the expression of IGFBP1, not IGFBP3 spines. Stimulated IGF-1 activity, thus enhancing RASFs proliferation, infiltration capacity and inhibiting apoptosis, results in the progress in the course of RA. The discovery of low expression of IGFBP1 in the RA synovial tissue also proved the suggestion. In addition, some people also found that the level of IGFBP1 expression in the blood of diabetic patients was obviously abnormal and the IGF-1 activity was significantly changed. The results of this study were also found in this study. It is suggested that TXNDC5 and the regulation of IGFBP1 expression may be an important molecular mechanism of the intrinsic link between RA and diabetes,.TXNDC5 negative regulation of IGFBP1 expression and the discovery of the function of RASFs cells, which provide a new idea for the study of the pathogenesis of RA.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R593.22

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3 滕玉芬;劉暉;庫爾班江;劉芳;武麗君;;幾種實(shí)驗(yàn)室指標(biāo)在類風(fēng)濕關(guān)節(jié)炎活動(dòng)中的評估[A];中華醫(yī)學(xué)會(huì)全國風(fēng)濕病學(xué)年會(huì)論文匯編[C];2003年

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9 馮興華;;中西醫(yī)結(jié)合治療類風(fēng)濕關(guān)節(jié)炎的思考[A];第六屆中國中西醫(yī)結(jié)合風(fēng)濕病學(xué)術(shù)會(huì)議論文匯編[C];2006年

10 劉喜德;張全祿;劉風(fēng)云;;抗環(huán)瓜氨酸肽抗體與類風(fēng)濕關(guān)節(jié)炎的相關(guān)性研究[A];浙江醫(yī)學(xué)會(huì)2007年風(fēng)濕病年會(huì)論文匯編[C];2007年

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