本文選題：T2D鼠 + 胰島素敏感性�。� 參考：《湖南師范大學(xué)》2015年博士論文

【摘要】：第一部分 成纖維生長因子21(FGF21)對糖尿病鼠的快速降糖作用目的：已有大量研究表明FGF21對糖代謝有調(diào)控作用,連續(xù)給藥7到14天后可以降低2型糖尿病型高血糖,還能增強(qiáng)胰島素的敏感性,降低胰島素抵抗。但很少有研究FGF21的快速降糖的作用�？焖俳堤菍τ谝愿哐菫椴l(fā)癥或者為主要危險因素的疾病例如急性創(chuàng)傷、炎癥以及心腦血管疾病等有重要的意義。方法：本實(shí)驗(yàn)先用溫州醫(yī)學(xué)院提供的人重組FGF21蛋白注射2型糖尿病小鼠(T2D小鼠)14天,用血糖試紙檢測小鼠隨機(jī)血糖。再用Elisa法檢測小鼠胰島素水平。之后,在注射FGF211小時后,用血糖試紙檢測小鼠血糖。結(jié)果：小鼠隨機(jī)血糖明顯下降并且增強(qiáng)了胰島素敏感性和降低了胰島素抵抗。注射FGF211小時后,T2D小鼠血糖和模擬應(yīng)激性高血糖小鼠血糖都明顯下降。提示FGF 21可能也有快速降低血糖的作用。第二部分 血清FGF21水平對腦內(nèi)FGF21表達(dá)水平的影響目的：有研究表明FGF21在患有心血管疾病、肝臟疾病、高血壓、肥胖、糖尿病等疾病時血清水平顯著增加。可能的機(jī)制是機(jī)體是對FGF21的信號傳導(dǎo)發(fā)生了障礙,對FGF21的敏感性減弱,才使FGF21過量表達(dá)。非常重要一點(diǎn)是有研究表明FGF21可以穿過血腦屏障(BBB)。但同時有研究發(fā)現(xiàn)FGF21需要通過細(xì)胞上的穿膜蛋白β-Klotho才能與成纖維因子受體(FGFR)結(jié)合而激活受體,這使FGF21的作用有組織選擇性。而FGF21是否能進(jìn)入大腦,大腦中是否有β-Klotho的表達(dá)和FGF21的受體激活機(jī)制還沒有研究。方法：本實(shí)驗(yàn)用Elisa法檢測非高血糖小鼠(ND小鼠)和2型糖尿病高血糖小鼠(T2D) FGF21血清水平。用western blot檢測ND小鼠的T2D小鼠的全腦蛋白做中FGF21表達(dá)水平。用western blot檢測靜脈注射外源性FGF21至小鼠后,同的時間點(diǎn)小鼠大腦的不同部位的FGF21、pFGFRl和β-Klotho的表達(dá)水平。結(jié)果：血清中FGF21在T2D小鼠中明顯高于ND小鼠。T2D小鼠大腦蛋白中的FGF21表達(dá)顯著性高于ND小鼠。靜脈注射外源性FGF21至小鼠后不同的時間點(diǎn)收集大腦蛋白,做western blot檢測,發(fā)現(xiàn)大腦不同部分FGF21的表達(dá)的和成纖維成長因子受體1(FGFR1)的磷酸化都發(fā)生了變化,并且檢測到了β-Klotho的表達(dá)。這表明了血清中FGF21的升高對大腦中FGF21的含量和FGFR1受體的激活有影響。但腦中FGF21的含量升高除了外源性FGF21直接進(jìn)入,是否還存在被誘導(dǎo)升高尚不清楚；FGFR1的磷酸化是FGF21直接激活還是FGF21誘導(dǎo)了其他FGF家族的因子升高而激活的也尚不能定論,但由于檢測到了β-Klotho的表達(dá),也有可能可以直接激活受體。這一結(jié)果表明FGF21可以穿過血腦屏障進(jìn)入大腦,也許可以直接作用于中樞神經(jīng)系統(tǒng)產(chǎn)生作用。第三部分 FGF21對腦內(nèi)皮細(xì)胞的影響目的：神經(jīng)保護(hù)不局限于神經(jīng)元細(xì)胞的保護(hù),對血腦屏障的保護(hù)也非常關(guān)鍵。血清中升高的FGF21直接接觸到血管內(nèi)皮細(xì)胞,但FGF21對血管內(nèi)皮細(xì)胞是否有保護(hù)作用目前以及保護(hù)機(jī)制沒有研究。在血管內(nèi)皮中FGF21的表達(dá)和損傷后的表達(dá)變化,傳導(dǎo)通路和作用機(jī)制,以及受體復(fù)合物形式都有待研究。方法：本研究應(yīng)用Western blot檢測FGF21在血管內(nèi)皮細(xì)胞中的表達(dá),缺氧缺糖(OGD)4小時再復(fù)氧復(fù)糖20小時候后FGF21的表達(dá)變化,以及血管內(nèi)皮細(xì)胞被重組FGF21蛋白處理后磷酸化FGFR1和β-Klotho的表達(dá)變化,是否對FGF21有時間依賴和劑量依賴。使用RNA干擾(SiRNA)技術(shù),轉(zhuǎn)染FGF21 SiRNA后用Western blot檢測分析,以確認(rèn)血管內(nèi)皮中FGF21細(xì)胞中的表達(dá)。轉(zhuǎn)染β-Klotho SiRNA后用Western blot和免疫熒光來觀察在β-Klotho基因沉默后,FGFR1能否被FGF21激活以及FGF21／磷酸化FGFRl/p-Klotho在血管內(nèi)皮細(xì)胞上是否共定位。用MTT檢測外源性FGF21能否對腦血管內(nèi)皮細(xì)胞在OGD 4小時復(fù)糖復(fù)氧20小時的損傷產(chǎn)生保護(hù)作用。用FITC檢測高糖炎癥損傷下FGF21對內(nèi)皮細(xì)胞滲透性保護(hù)。用western blot檢測FGF21通過誘導(dǎo)哪個蛋白升高來進(jìn)行保護(hù)作用。結(jié)果：首次發(fā)現(xiàn)腦血管內(nèi)皮細(xì)胞中FGF21有表達(dá)且能被細(xì)胞缺氧缺糖后再灌注損傷誘導(dǎo)表達(dá)增加。FGF21在腦血管內(nèi)皮細(xì)胞中能激活FGFR1磷酸化并同時誘導(dǎo)β-Klotho表達(dá)增高,且FGF21／磷酸化FGFR1/β-Klotho這三者是在細(xì)胞是是共定位的。但在β-Klotho基因沉默后FGF21不能激活FGFR1。這一結(jié)果說明了在除了脂肪細(xì)胞,在腦血管內(nèi)皮細(xì)胞中,FGF21的傳導(dǎo)通路也是通過FGF21/FGFR1/βKlotho三聚體復(fù)合物的形成,激活FGFR1磷酸化而進(jìn)行信號傳導(dǎo)的。這是首次發(fā)現(xiàn)FGF21在非脂肪細(xì)胞組織,在腦內(nèi)皮細(xì)胞中也是通過FGF21/FGFR1/β-Klotho三聚體復(fù)合物進(jìn)行信號傳導(dǎo)的,提示這也許是FGF21信號傳導(dǎo)的共性。并且外源性FGF21對腦血管內(nèi)皮細(xì)胞的缺氧缺糖后再灌注損傷和高糖合并炎癥損傷都有保護(hù)作用。FGF21還對內(nèi)皮細(xì)胞在高糖合并炎癥損傷下減少其通透性的保護(hù)作用,其作用是通過誘導(dǎo)升高PPARγ實(shí)現(xiàn)的。FGF21還可以升高細(xì)胞膜連接蛋白ZO-1、VE-Cadherin連減少細(xì)胞通透性。第四部分： FGF21對神經(jīng)元細(xì)胞的影響目的：之前的實(shí)驗(yàn)證實(shí)了FGF21能穿過血腦屏障,而神經(jīng)元作為最重要的神經(jīng)功能性細(xì)胞,FGF21對神經(jīng)元細(xì)胞能否產(chǎn)生保護(hù)作用還沒有研究。并且FGF21在神經(jīng)元細(xì)胞中有無表達(dá),或能否對FGF21的刺激產(chǎn)生反應(yīng),以及FGF21在神經(jīng)元細(xì)胞的受體和信號傳導(dǎo)通路是什么。都還有待研究。方法：本研究應(yīng)用Western blot檢測分析小鼠原代培養(yǎng)大腦皮層神經(jīng)元細(xì)胞正常情況下和缺氧后的FGF21表達(dá)變化,和小鼠原代培養(yǎng)神經(jīng)元細(xì)胞被重組FGF21蛋白處理后磷酸化纖維生長因子受體1(FGFR1)和β-Klotho的表達(dá)變化,是否對FGF21有時間依賴和劑量依賴。用免疫熒光染色檢測磷酸化FGFR1和β-Klotho能否被FGF21誘導(dǎo)和是否與FGF21共定位。用C-IP和Western blot檢測分析FGF21是否能與FGFR1和β-Klotho形成三聚體復(fù)合物。用LDH檢測外源性FGF21蛋白能否對小鼠原代培養(yǎng)神經(jīng)元細(xì)胞缺氧或高糖損傷時產(chǎn)生保護(hù)作用。結(jié)果：小鼠原代培養(yǎng)神經(jīng)元細(xì)胞正常情況下FGF21的表達(dá)量極低,但在缺氧損傷后FGF21能被誘導(dǎo)表達(dá)增加。在小鼠原代培養(yǎng)神經(jīng)元細(xì)胞中可以看到FGF21/磷酸化FGFR1/β-Klotho是共定位的,且FGFR1被FGF21激活磷酸化。在小鼠原代培養(yǎng)神經(jīng)元細(xì)胞正常狀態(tài)下,FGF21表達(dá)量太低,并不會形成FGF21/FGFR1/β-Klotho三聚體復(fù)合物,FGFR1/β-Klotho也不會形成二聚體復(fù)合物。但小鼠原代培養(yǎng)神經(jīng)元細(xì)胞被重組FGF21蛋白處理后,可以觀測到FGF21/FGFR1/β—Klotho三聚體復(fù)合物的形成。這一結(jié)果可以證明在小鼠原代培養(yǎng)神經(jīng)元細(xì)胞中,FGF21的傳導(dǎo)通路與脂肪細(xì)胞中和之前實(shí)驗(yàn)的腦內(nèi)皮細(xì)胞一樣,都是通過FGF21/FGFR1/β-Klotho三聚體復(fù)合物的形成,激活FGFR1磷酸化而進(jìn)行信號傳導(dǎo)的。并且外源性FGF21對小鼠原代培養(yǎng)神經(jīng)元細(xì)胞在缺氧和高糖的損傷下都有保護(hù)作用。
[Abstract]:The first part is the rapid hypoglycemic effect of fibroblast growth factor 21 (FGF21) on diabetic rats: a large number of studies have shown that FGF21 has a regulatory effect on glucose metabolism. Continuous administration of drugs for 7 to 14 days can reduce type 2 diabetes type hyperglycemia, enhance insulin sensitivity and lower insulin resistance. But few studies have studied the rapid decline of FGF21. The effect of sugar is of great significance for high blood sugar as a complication or a major risk factor such as acute trauma, inflammation, and cardiovascular and cerebrovascular diseases. Methods: this experiment first injected the recombinant FGF21 protein from the Wenzhou Medical College (T2D mice) to test the mice with blood glucose test paper for 14 days. Elisa method was used to detect the insulin level in mice. After the injection of FGF211 hours, the blood glucose of mice was detected with blood glucose test paper. Results: the blood glucose of mice was obviously decreased and the insulin sensitivity was increased and the insulin resistance was reduced. After FGF211 hours, the blood glucose of T2D rats and the simulated stress hyperglycemia mice blood sugar The effect of FGF 21 may also have a rapid decrease in blood sugar. Second the effect of serum level of FGF21 on the level of FGF21 expression in the brain: a study shows that FGF21 has a significant increase in blood level in diseases such as cardiovascular disease, liver disease, hypertension, obesity, diabetes and other diseases. The possible mechanism is that the body is a FGF21 The signal transduction was impaired and the sensitivity of FGF21 weakened to overexpression of FGF21. It was very important that research showed that FGF21 could pass through the blood brain barrier (BBB). But at the same time, it was found that FGF21 needed to bind to the fibroblast receptor (FGFR) through the membrane protein beta -Klotho on the cell to activate the receptor, which made FGF21 Whether or not FGF21 can enter the brain, whether there is the expression of beta -Klotho in the brain and the mechanism of FGF21 receptor activation have not yet been studied. Methods: the Elisa assay was used to detect the level of FGF21 blood in non hyperglycemic mice (ND mice) and type 2 diabetic hyperglycemia mice (T2D). Western blot was used to detect T2D mice in ND mice. The expression level of FGF21 in the whole brain protein. The expression level of FGF21, pFGFRl and beta -Klotho in different parts of the brain of mice was detected at the same time point after intravenous injection of exogenous FGF21 to mice by Western blot. Results: the significance of FGF21 in serum in T2D mice was significantly higher than that in.T2D mice of ND mice. The brain protein was collected at different time points after intravenous injection of exogenous FGF21 to mice. Western blot detection was performed. The phosphorylation of FGF21 in different parts of the brain and phosphorylation of fibroblast growth factor receptor 1 (FGFR1) were changed, and the expression of beta -Klotho was detected. This indicates that the elevation of FGF21 in the serum to FGF2 in the brain. The content of 1 and the activation of FGFR1 receptors are affected. But the increase in the content of FGF21 in the brain is not clear except for the direct entry of exogenous FGF21. The activation of FGFR1 phosphorylation is directly activated by FGF21 or by FGF21 induced factors in the FGF family, but it is still inconclusive, but as a result of the detection of beta -Klotho The expression may also activate the receptor directly. This results suggest that FGF21 can penetrate the blood brain barrier into the brain, perhaps directly acting on the role of the central nervous system. Third part of the effect of FGF21 on the brain endothelial cells: neuroprotection is not limited to the protection of neuronal cells and the protection of the blood brain barrier is also not It is often crucial that the elevated FGF21 in the serum is directly exposed to vascular endothelial cells, but the protective mechanism of FGF21 on vascular endothelial cells and the protective mechanism are not studied. The expression of FGF21 in the vascular endothelium and the change of expression after injury, the transduction pathway and mechanism of action, and the form of receptor complex are still to be studied. Methods: Western blot was used to detect the expression of FGF21 in vascular endothelial cells, the changes of FGF21 expression after 4 hours of anoxic glucose deficiency (OGD) and 20 reoxygenated reoxygenation, and the changes in the expression of phosphorylated FGFR1 and beta -Klotho after the recombinant FGF21 protein was treated by recombinant FGF21 protein. SiRNA) technology, after transfection of FGF21 SiRNA, Western blot was used to detect the expression in FGF21 cells in vascular endothelial cells. After transfection of beta -Klotho SiRNA, Western blot and immunofluorescence were used to observe whether FGFR1 could be activated after beta -Klotho gene silencing and whether or not it was co determined on vascular endothelial cells. The protective effect of exogenous FGF21 on the damage of cerebral vascular endothelial cells at OGD 4 hours complex of reoxygenation for 20 hours was detected by MTT. FITC was used to detect the permeability of FGF21 to endothelial cells under high glucose inflammation. Western blot was used to detect the protective effect of FGF21 by inducing which protein to increase. Results: the first discovery of brain blood FGF21 is expressed in endothelial cells and can be induced by reperfusion injury induced by anoxia and glucose deficiency..FGF21 can activate FGFR1 phosphorylation in cerebral vascular endothelial cells and induce higher expression of beta -Klotho, and FGF21 / phosphorylation of FGFR1/ beta -Klotho, these three are Co located in cells, but after the silence of the beta -Klotho gene, FGF21 The failure to activate FGFR1. shows that in the brain vascular endothelial cells, the conduction pathway of FGF21 is also transmitted through the formation of the FGF21/FGFR1/ beta Klotho tripolymer complex in the brain vascular endothelial cells, activating FGFR1 phosphorylation and signaling. This is the first time that FGF21 is found in non adipocyte tissue, and in the brain endothelial cells is also through FGF2. The signal transduction of 1/FGFR1/ beta -Klotho trimer complexes suggests that this may be the commonality of FGF21 signal transduction. And exogenous FGF21 has protective effects on reperfusion injury after hypoxia and glucose deficiency and high glucose combined with inflammatory injury in cerebral vascular endothelial cells, and.FGF21 also reduces the permeability of endothelial cells under high glucose and inflammatory injury. The protective effect is that.FGF21 can increase the cell membrane connexin ZO-1 by inducing the increase of PPAR gamma, and VE-Cadherin even reduces cell permeability. The fourth part: the effect of FGF21 on neuron cells: previous experiments confirmed that FGF21 could pass through the blood brain barrier, and the neuron was the most important neural functional fine. There is no study on the protective effect of FGF21 on neuron cells. And whether FGF21 is expressed in neuron cells, or whether it can react to the stimulation of FGF21, and what the receptor and signal transduction pathway of FGF21 in the neuron cells are all still to be studied. Methods: This study used Western blot to detect and analyze the original mice. The changes in FGF21 expression in normal and anoxic neurons of cerebral cortex, and the changes in the expression of phosphorylated fibroblast growth factor receptor 1 (FGFR1) and beta -Klotho after the recombinant FGF21 protein were treated by recombinant FGF21 protein in the primary cultured neurons of the mice, were dependent on the time dependence and dose dependence on FGF21. The phosphorylated FGF was detected by immunofluorescence staining. Whether R1 and beta -Klotho can be induced by FGF21 and co location with FGF21. Use C-IP and Western blot to detect whether FGF21 can form a trimer complex with FGFR1 and beta -Klotho. The expression of FGF21 is very low in normal neuron cells, but the expression of FGF21 can be induced to increase after the hypoxia injury. In the primary cultured neuron cells of the mice, the FGF21/ phosphorylation FGFR1/ beta -Klotho is Co located, and FGFR1 is activated by FGF21 phosphorylation. The expression of FGF21 in the normal state of the primary cultured neuron cells in mice. The amount is too low to form a FGF21/FGFR1/ beta -Klotho trimer complex and FGFR1/ beta -Klotho does not form a two polymer complex. But the primary cultured neuron cells of mice can be treated with the recombinant FGF21 protein, and the formation of FGF21/FGFR1/ beta Klotho trimer complex can be observed. This result can prove that the primary cultured nerve in mice can be cultured. In the cell, the conduction pathway of FGF21 is the same as that of the adipocytes and the previous experimental endothelium cells, all through the formation of the FGF21/FGFR1/ beta -Klotho trimer complex, activating FGFR1 phosphorylation and conducting signal transduction. And exogenous FGF21 protects the primary cultured neurons of mice under the damage of hypoxia and high glucose. Use.

【學(xué)位授予單位】：湖南師范大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R587.1

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9 苑t，

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