本文選題：microRNA + 糖尿病視網(wǎng)膜病變�。� 參考：《第二軍醫(yī)大學(xué)》2010年博士論文

【摘要】： 目的： 觀察鏈脲佐菌素(STZ)誘導(dǎo)的糖尿病(DM)大鼠早期視網(wǎng)膜的形態(tài)學(xué)改變,評(píng)價(jià)其作為早期糖尿病視網(wǎng)膜病變(DR)動(dòng)物模型的應(yīng)用價(jià)值；測(cè)定DM大鼠視網(wǎng)膜VEGF mRNA和PEDF mRNA于不同時(shí)間點(diǎn)的表達(dá)情況,探討二者間的相互關(guān)系及其對(duì)于DR發(fā)生發(fā)展的相關(guān)意義,并從細(xì)胞因子角度進(jìn)一步評(píng)價(jià)STZ-DM大鼠作為早期DR動(dòng)物模型的應(yīng)用價(jià)值。以lOw STZ-DM大鼠作為早期DR動(dòng)物模型,檢測(cè)視網(wǎng)膜microRNAs (miRNAs)的表達(dá)差異譜,并初步探討其在DR發(fā)生發(fā)展過(guò)程中的作用。 方法： 64只體重180±20g雄性SD大鼠隨機(jī)分為CON組和DM組各32只,DM組按60mg／kg體質(zhì)量腹腔注射STZ 1次建立DM大鼠模型；CON組腹腔注射等量檸檬酸緩沖液作為對(duì)照。DM成膜后每周測(cè)量各組體質(zhì)量、血糖等一般生理指標(biāo),并于2w、4w、6w、8w和10w各時(shí)間點(diǎn)隨機(jī)抽樣行視網(wǎng)膜實(shí)時(shí)定量PCR(qRT-PCR)檢測(cè)視網(wǎng)膜VEGF mRNA、PEDF mRNA的表達(dá)豐度。10w時(shí)各組隨機(jī)抽樣對(duì)視網(wǎng)膜組織進(jìn)行HE染色、FITC-Dextran灌注視網(wǎng)膜血管鋪片及透射電鏡超微結(jié)構(gòu)觀察；免疫組化染色檢測(cè)視網(wǎng)膜VEGF及PEDF的表達(dá)強(qiáng)度及部位；miRNA基因芯片篩選DM組與CON組視網(wǎng)膜表達(dá)顯著差異的miRNAs。qRT-PCR檢測(cè)目的miRNAs于每個(gè)時(shí)間點(diǎn)在視網(wǎng)膜中的表達(dá)豐度。并通過(guò)生物信息學(xué)分析預(yù)測(cè)表達(dá)差異顯著miRNAs的可能靶基因。 結(jié)果： 1.STZ腹腔注射DM成模率100%。注射前DM組平均體質(zhì)量(187.5±5.4g)與CON組(185.0±6.9g)差異不顯著(P0.05)；STZ腹腔注射后,DM組體質(zhì)量增加不明顯,后期甚至有所減輕,CON組體質(zhì)量逐步增長(zhǎng),10w時(shí)DM組平均體質(zhì)量(169.9±26.9g)與CON組(439.2±23.5g)差異顯著(P0.001)。注射前DM組平均血糖(6.49±0.68mmol/l)與CON組(6.60±0.59mmol/L)差異不顯著(P0.05)；STZ腹腔注射72h后,DM組平均血糖(26.63±4.54mmol／l)與CON組(6.37±0.49mmol／l)差異顯著(P0.001),～10wDM組血糖均16.7mmol／l,CON組保持在5.6～7.4mmol／l。視網(wǎng)膜HE染色顯示10w DM組大鼠視網(wǎng)膜毛細(xì)血管擴(kuò)張,間質(zhì)水腫；CON組視網(wǎng)膜未見(jiàn)明顯異常。FITC-Dextran灌注視網(wǎng)膜顯示10w DM組血管迂曲,管徑不規(guī)則,未見(jiàn)毛細(xì)血管熒光滲漏、微血管瘤、視網(wǎng)膜無(wú)灌注區(qū)等；CON組血管管徑均勻一致、分支自然流暢。透射電鏡下DM組視網(wǎng)膜超微結(jié)構(gòu)的改變主要有：毛細(xì)血管基底膜增厚,內(nèi)皮細(xì)胞指狀突起,線粒體腫脹、嵴脫落、空泡樣變；周細(xì)胞線粒體腫脹、嵴脫落、空泡樣變；內(nèi)核層雙極細(xì)胞線粒體腫脹、嵴脫落、空泡樣變；感光細(xì)胞膜盤間隙增寬、數(shù)量減少；神經(jīng)節(jié)細(xì)胞線粒體腫脹、嵴脫落、空泡樣變。 2.經(jīng)qRT-PCR檢測(cè),CON組視網(wǎng)膜有VEGF mRNA表達(dá),表達(dá)量隨時(shí)間無(wú)明顯變化；DM組VEGF mRNA的表達(dá),2w時(shí)較CON組有所增高,至6w表達(dá)量約為CON組的3倍(P0.05),10w表達(dá)量增高到CON組的6倍(P0.001)。PEDF mRNA也表達(dá)于CON組視網(wǎng)膜,DM組2w時(shí)的表達(dá)量較CON組有所減少,至4w其表達(dá)量約為CON組的1／2(P0.001),10w表達(dá)量降至CON組的1／3(P0.001)。視網(wǎng)膜免疫組化染色觀察,CON組：VEGF主要分布于內(nèi)核層和節(jié)細(xì)胞層,PEDF主要分布于內(nèi)核層和節(jié)細(xì)胞層,其余各層也可見(jiàn)陽(yáng)性表達(dá)；DM組VEGF表達(dá)較CON組明顯增強(qiáng),視網(wǎng)膜各層神經(jīng)細(xì)胞均見(jiàn)有強(qiáng)陽(yáng)性表達(dá)；PEDF表達(dá)較CON組明顯減弱,其分布主要位于節(jié)細(xì)胞層及內(nèi)叢狀層。 3.miRNA芯片檢測(cè)結(jié)果顯示：和CON組比較,DM組共有168個(gè)miRNAs的表達(dá)出現(xiàn)明顯變化。其中,主要有miR-182、miR-96、miR-183、miR-211、miR-204、miR-124、miR-592、miR-190b、miR-502-3p、miR-363、miR-29c*、miR-210等表達(dá)顯著上調(diào)；miR-10b、miR-10a、miR-219-2-3p、miR-144、miR-338、miR-199a、miR-451、miR-34a、miR-542-5p、miR-142-3p、miR-223、miR-18a等表達(dá)顯著下調(diào)。經(jīng)qRT-PCR檢測(cè),大部分表達(dá)上調(diào)的miRNAs在視網(wǎng)膜中的表達(dá)量隨病程發(fā)展逐漸上升；表達(dá)下調(diào)的12個(gè)miRNAs的表達(dá)量隨病程發(fā)展均逐漸下降。生物信息學(xué)分析結(jié)果顯示,這些表達(dá)顯著差異的miRNAs可以調(diào)控許多與DR密切相關(guān)基因的表達(dá),如miR-29c*、miR-199a可能靶向VEGFa,miR-363可能靶向PEDF,等等。 結(jié)論： 1.STZ誘導(dǎo)的DM大鼠在病程10w時(shí)即已出現(xiàn)類似早期DR的相關(guān)改變,可作為人類早期背景型糖尿病視網(wǎng)膜病變(background diabetic retinopathy, BDR)的動(dòng)物模型以用于DR的相關(guān)實(shí)驗(yàn)研究,并且該造模方法簡(jiǎn)單經(jīng)濟(jì)、用時(shí)較短、重復(fù)性好、成功率高。 2.作為主要血管生成刺激因子的VEGF和潛在血管生成抑制因子的PEDF,二者間的動(dòng)態(tài)平衡對(duì)調(diào)節(jié)血管滲漏與新生血管形成起著至關(guān)重要的作用。生理狀態(tài)下,VEGF在視網(wǎng)膜中呈低表達(dá),而PEDF相對(duì)占有優(yōu)勢(shì),這對(duì)維持視網(wǎng)膜血管完整、抑制新生血管形成是非常必要的。10w DM大鼠視網(wǎng)膜VEGF表達(dá)增多、PEDF減少,破環(huán)了二者間的平衡關(guān)系,繼而可能導(dǎo)致視網(wǎng)膜出現(xiàn)血管滲漏和新生血管等。這就說(shuō)明VEGF與PEDF的失衡可能是造成DR發(fā)生發(fā)展的重要因素之一,同時(shí)也從細(xì)胞因子角度進(jìn)一步證明了10w STZ-DM大鼠可作為早期BDR的動(dòng)物模型。 3.早期BDR大鼠模型視網(wǎng)膜中,miRNAs的表達(dá)譜較正常對(duì)照有明顯差異；在這些表達(dá)明顯差異的miRNAs中,有些隨病程發(fā)展表達(dá)量逐漸上升,還有些隨病程發(fā)展逐漸下降；這些表達(dá)差異的miRNAs可能靶向許多與DR發(fā)生發(fā)展密切相關(guān)的基因。提示：miRNAs在DR發(fā)生發(fā)展過(guò)程中可能起著重要的調(diào)控作用。
[Abstract]:Objective:
To observe the morphological changes of the early retina of streptozotocin (STZ) induced diabetic (DM) rats and evaluate its application as an animal model of early diabetic retinopathy (DR); to determine the expression of VEGF mRNA and PEDF mRNA in the retina of DM rats at different time points and to explore the relationship between the two and the occurrence of DR in the rats. The significance of the development was further evaluated from the angle of cytokine, and the value of STZ-DM rats as an early DR animal model was further evaluated. The lOw STZ-DM rat was used as an early DR animal model to detect the differential expression of microRNAs (miRNAs) in the retina, and to explore its role in the development of DR.
Method:
64 male SD rats weighing 180 20g were randomly divided into CON group and 32 DM group. DM group was injected with STZ 1 times to establish DM rat model according to 60mg / kg mass intraperitoneally, and the CON group was injected with equal amount of citric acid buffer as a control.DM membrane. Retina real-time quantitative PCR (qRT-PCR) was used to detect retinal VEGF mRNA and PEDF mRNA expression in.10w. The retinal tissue was stained with HE, the retinal vascular spread and transmission electron microscopy were observed by random sampling, and the expression intensity and location of retina VEGF and PEDF were detected by immunohistochemical staining. IRNA gene chip screened the expression abundance of miRNAs at each time point in the retina of the retina, which was significantly different between the DM group and the CON group, and predicted the possible target genes for the significant miRNAs expression by bioinformatics analysis.
Result:
The average body mass (187.5 + 5.4G) and CON group (185 + 6.9g) before 100%. injection of 100%. was not significant (P0.05). After STZ intraperitoneal injection, the mass increase of the DM group was not obvious, the latter even decreased, the mass of CON group increased gradually, and the average body mass of the group (169.9 +) was significantly different from that of the group (439.2 + 439.2). (P0.001). The average blood glucose (6.49 + 0.68mmol/l) and CON group (6.60 + 0.59mmol/L) before the injection were not significant (P0.05). After STZ intraperitoneal injection of 72h, the average blood glucose (26.63 + 4.54mmol / L) in the DM group was significantly different from that of the CON group (6.37 + CON). The retinal capillary dilatation and interstitial edema in the 10W DM group showed that there was no obvious abnormal.FITC-Dextran perfusion retina in group CON showed that the vascular circuitous in group 10W DM, irregular tube diameter, no capillary fluorescent leakage, microangioma, and retinal instillation area, and the vascular diameter of the CON group was uniform, and the branch was natural and fluent. Transmission electricity. Transmission electricity The ultrastructural changes in the retina of the DM group were mainly: the thickening of the capillary basement membrane, the finger like protruding of the endothelial cells, the swelling of the mitochondria, the exfoliation of the crista, the vacuoles like changes, the swelling of the mitochondria in the pericytes, the exfoliation of the crista, the vacuoles, the widening of the membrane disks of the photoreceptor cells, the widening of the membrane disc in the photoreceptor cells, and the decrease in the number of the photoreceptor cells. The mitochondria of the ganglion cells were swollen, the ridges were shedding and vacuoles changed.
2. by qRT-PCR, the expression of VEGF mRNA in the retina of group CON was not changed with time. The expression of VEGF mRNA in group DM was higher than that in CON group, and the expression amount of 6W was about 3 times of CON group (P0.05), and the expression amount increased to 6 times of the retina. The expression of 4W was about 1 / 2 (P0.001) in group CON and 1 / 3 (P0.001) in CON group. CON group: VEGF mainly distributed in the kernel layer and ganglion layer, PEDF mainly in the kernel layer and the ganglion layer, and the other layers were also positive, and VEGF expression in DM group was obviously enhanced than that of CON group. There were strong positive expression of neurons in all layers of the retina, and the expression of PEDF was significantly lower than that in CON group. The distribution was mainly in the ganglion cell layer and the inner plexiform layer.
The results of 3.miRNA chip detection show that compared with the CON group, there are 168 miRNAs expressions in the group DM, including miR-182, miR-96, miR-183, miR-211, miR-204, miR-124, miR-592. 51, miR-34a, miR-542-5p, miR-142-3p, miR-223, miR-18a and other expressions were significantly downregulated. By qRT-PCR, the expression of most of the up regulated miRNAs in the retina increased with the course of disease, and the expression of 12 miRNAs expressed down gradually decreased with the development of the disease. Bioinformatics analysis showed that these expressions were significantly poor. Different miRNAs can regulate many DR related genes expression, such as miR-29c*, miR-199a may target VEGFa, miR-363 may target PEDF, and so on.
Conclusion:
1.STZ induced DM rats had related changes similar to early DR during the course of disease 10W, which could be used as the animal model of background diabetic retinopathy (BDR) for early human background diabetic retinopathy (BDR) for the experimental study of DR, and the modeling method was simple, short, reproducible, and high success rate.
2. as the VEGF of the major vascular stimulation factors and the PEDF of the potential angiogenesis inhibitor, the dynamic balance between the two plays a vital role in regulating vascular leakage and neovascularization. In physiological state, VEGF is low in the retina, while PEDF is relatively dominant, which is new to the maintenance of retinal blood vessels. Angiogenesis is essential for the increase of VEGF expression in the retina of.10w DM rats, the decrease of PEDF, the equilibrium relationship between the two and the retinal vascular leakage and the neovascularization in the retina. This indicates that the imbalance of VEGF and PEDF may be one of the important factors that cause the development of DR, and also from the angle of cytokine. One step proves that 10W STZ-DM rats can be used as animal models of early BDR.
The expression profiles of miRNAs in the retina of the BDR rat model of the early 3. were significantly different than that in normal controls. In these miRNAs, some of these expressions were gradually increasing with the development of the disease course, and some of them decreased with the development of the disease. These differentially expressed miRNAs may be targeted to many genes closely related to the development of DR. MiRNAs may play an important regulatory role in the development of DR.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R774.1

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