【摘要】：研究目的腦中風(fēng),是近年來(lái)世界上導(dǎo)致長(zhǎng)期致殘和死亡的主要原因,具有發(fā)病率高,死亡率高,致殘率高和復(fù)發(fā)率高的特點(diǎn)。其中,相比于出血性腦中風(fēng),缺血性腦中風(fēng)更常見(jiàn),所占比例超過(guò)80%,是由于大腦動(dòng)脈阻塞從而阻斷血液流向大腦導(dǎo)致組織壞死。缺血性腦中風(fēng)也就是腦缺血的病理生理過(guò)程是復(fù)雜的、廣泛的,包括氧化應(yīng)激,興奮性氨基酸毒性作用,能量代謝障礙,細(xì)胞離子動(dòng)態(tài)平衡的改變,細(xì)胞內(nèi)鈣水平增加,活性氧介導(dǎo)的毒性,炎癥細(xì)胞因子介導(dǎo)的細(xì)胞毒性作用等。最近的研究結(jié)果表明先天免疫系統(tǒng)的炎癥反應(yīng)與腦缺血發(fā)病過(guò)程和進(jìn)展密切相關(guān)。先天免疫系統(tǒng)是限制宿主不受損傷的第一道防線,細(xì)胞內(nèi)和細(xì)胞外含有模式識(shí)別受體(PRRs),它們可以檢測(cè)到急性損傷,從而啟動(dòng)炎癥反應(yīng)。核苷酸結(jié)合寡聚化結(jié)構(gòu)域(NOD)——樣受體(NLRs)是細(xì)胞內(nèi)模式識(shí)別受體家族的一個(gè)成員,在炎癥反應(yīng)中發(fā)揮關(guān)鍵作用。在人類22類NLRs中14類包含熱蛋白結(jié)構(gòu)域并形成NLRP亞型(NLRPs)。在NLRPs家族中,一些成員如NLRP1,NLRP3,NLRP6等已經(jīng)被深入研究,它們可以通過(guò)結(jié)合蛋白ASC招募pro-caspase-1,激活炎性小體,使無(wú)活性的pro-caspase-1激活為成熟的caspase-1,從而導(dǎo)致IL-1β和IL-18的產(chǎn)生和釋放并引發(fā)炎癥反應(yīng)。最近一項(xiàng)研究表明體外培養(yǎng)的人類星形膠質(zhì)細(xì)胞表達(dá)NLRP2炎性小體,而NLRP2在體內(nèi)的分布和作用卻很少研究,特別是在中樞神經(jīng)系統(tǒng)。那么NLRP2是否在體內(nèi)中樞神經(jīng)系統(tǒng)中表達(dá)以及是否與腦缺血等神經(jīng)系統(tǒng)疾病相關(guān)仍需進(jìn)一步探討。在本次實(shí)驗(yàn)研究中,通過(guò)建立在體大腦中動(dòng)脈栓塞(MCAO)模型和培養(yǎng)細(xì)胞的糖氧剝奪(OGD)模型從體內(nèi)和體外兩方面來(lái)探究NLRP2在腦缺血中的作用及可能的機(jī)制。研究方法1 NLRP2在小鼠腦缺血后的表達(dá)變化1.1 C57BL/6野生型小鼠腦缺血模型的構(gòu)建及神經(jīng)學(xué)評(píng)分1.1.1選取小鼠并構(gòu)建缺血模型選取雄性野生型C57BL/6實(shí)驗(yàn)小鼠,體重23g左右,建立大腦中動(dòng)脈栓塞模型。頸部正中切口,切開皮膚,在顯微鏡下鈍性分離出左側(cè)頸總動(dòng)脈,頸內(nèi)動(dòng)脈及頸外動(dòng)脈,將尼龍線栓小心插入頸總動(dòng)脈,當(dāng)腦血流儀檢測(cè)到血流突然下降時(shí)停止繼續(xù)插入,并開始計(jì)時(shí),12、24、48小時(shí)后處死小鼠取材。1.1.2通過(guò)神經(jīng)學(xué)評(píng)分評(píng)價(jià)模型是否建立成功。1.2腦缺血后NLRP2在小鼠腦中的表達(dá)變化及分布1.2.1使用蛋白質(zhì)免疫印跡法(western blot,WB)、Real-time PCR和免疫組織化學(xué)法(immunohistochemistry,IHC)檢測(cè)在腦缺血后NLRP2的表達(dá)變化情況。1.2.2采用組織免疫熒光(immunofluorescence,IF)方法對(duì)NLRP2與小鼠大腦的不同細(xì)胞的標(biāo)記物蛋白進(jìn)行熒光雙染檢測(cè)NLRP2在腦中的分布。1.3體外模型的構(gòu)建及NLRP2的檢測(cè)體外培養(yǎng)原代星形膠質(zhì)細(xì)胞,建立糖氧剝奪(Oxygen Glucose Deprivation,OGD)模型,分別進(jìn)行OGD處理0.5、1、1.5、2h,使用蛋白質(zhì)免疫印跡法(western blot,WB)、組織免疫熒光(immunofluorescence,IF)和 Real-time PCR 檢測(cè)OGD后原代星形膠質(zhì)細(xì)胞中NLRP2的表達(dá)變化。2 NLRP2在小鼠腦缺血損傷中的作用2.1注射腺相關(guān)病毒沉默小鼠腦內(nèi)NLRP2基因利用腦立體定位注射技術(shù)將攜帶NLRP2沉默基因的腺相關(guān)病毒載體注射到神經(jīng)系統(tǒng)的特定部位,以沉默這個(gè)部位的NLRP2基因。2.2注射空病毒與注射攜帶NLRP2沉默基因的小鼠大腦形態(tài)學(xué)損傷對(duì)比注射空病毒與注射攜帶NLRP2沉默基因的小鼠腦缺血后處理,對(duì)注射空病毒與注射攜帶NLRP2沉默基因的小鼠大腦進(jìn)行TTC染色,并對(duì)其形態(tài)學(xué)損傷進(jìn)行評(píng)分。2.3小鼠腦缺血模型中炎癥因子的檢測(cè)利用CBA、Real-time PCR方法檢測(cè)注射空病毒與注射攜帶NLRP2沉默基因的小鼠大腦勻漿中促炎因子的含量。2.4 NLRP2對(duì)OGD誘導(dǎo)的原代星形膠質(zhì)細(xì)胞凋亡的影響2.4.1對(duì)星形膠質(zhì)細(xì)胞進(jìn)行轉(zhuǎn)染2.4.2星形膠質(zhì)細(xì)胞的凋亡檢測(cè)對(duì)轉(zhuǎn)染si-NLRP2的星形膠質(zhì)細(xì)胞進(jìn)行OGD處理,Annexin V/PI染色后,使用流式細(xì)胞儀檢測(cè)OGD處理?xiàng)l件下,原代星形膠質(zhì)細(xì)胞凋亡的影響。3腦缺血損傷中NLRP2通路的調(diào)控作用WB檢測(cè)小鼠腦缺血后NLRP2對(duì)小鼠大腦caspase-1、ASC、IL-1β等相關(guān)蛋白水平的影響。WB檢測(cè)NLRP2對(duì)注射空病毒與注射攜帶NLRP2沉默基因的病毒小鼠大腦caspase-1、ASC、IL-1β等相關(guān)蛋白水平。WB檢測(cè)轉(zhuǎn)染空si-RNA和轉(zhuǎn)染si-NLRP2的星形膠質(zhì)細(xì)胞OGD處理后,NLRP2對(duì)caspase-1、p-p65、IL-1β等蛋白表達(dá)的影響。研究結(jié)果1小鼠腦缺血后NLRP2及其下游分子在腦內(nèi)的表達(dá)及作用1.1 C57BL/6小鼠腦缺血模型的構(gòu)建及神經(jīng)學(xué)評(píng)分由于死亡或者是神經(jīng)學(xué)評(píng)分小于2分,每組大約有l(wèi)5%小鼠被剔除。1.2腦缺血后NLRP2在小鼠腦中的表達(dá)變化及分布1.2.1使用蛋白質(zhì)免疫印跡法(western blot,WB)、Real-time PCR和免疫組織化學(xué)法(immunohistochemistry,IHC)檢測(cè)腦缺血后NLRP2的表達(dá)變化,通過(guò)WB、Real-time PCR分析,我們發(fā)現(xiàn)NLRP2在腦缺血后表達(dá)明顯升高,并且在24小時(shí)達(dá)到高峰,免疫組化結(jié)果也證明這一點(diǎn)。1.2.2通過(guò)免疫熒光染色得出,NLRP2主要表達(dá)于原代星形膠質(zhì)細(xì)胞,在神經(jīng)元中也有少量表達(dá),在小膠質(zhì)細(xì)胞中幾乎沒(méi)有表達(dá)。1.3體外模型的構(gòu)建及NLRP2的檢測(cè)體外培養(yǎng)原代星形膠質(zhì)細(xì)胞,建立糖氧剝奪OGD模型,通過(guò)WB、Real-time PCR結(jié)果分析,我們發(fā)現(xiàn)OGD后NLRP2表達(dá)明顯升高,并且在OGD1.5小時(shí)達(dá)到高峰,免疫熒光結(jié)果顯示細(xì)胞OGD1.5小時(shí)后,NLRP2表達(dá)升高。2 NLRP2在小鼠腦缺血損傷中的作用2.1注射腺相關(guān)病毒沉默小鼠腦內(nèi)NLRP2基因注射病毒4周后,OCT包埋小鼠大腦組織,冰凍切片于顯微鏡下觀察病毒侵染范圍,范圍較大,覆蓋了大腦中動(dòng)脈所支配的區(qū)域。2.2注射空病毒與注射攜帶NLRP2沉默基因的病毒小鼠大腦形態(tài)學(xué)損傷對(duì)比TTC染色結(jié)果顯示,注射NLRP2沉默基因腦缺血后,小鼠神經(jīng)學(xué)評(píng)分明顯降低,腦梗死面積也明顯減少,。2.3小鼠腦缺血模型中炎癥因子的檢測(cè)對(duì)注射空病毒和注射NLRP2沉默基因的病毒的小鼠進(jìn)行腦缺血處理,CBA、Real-time PCR結(jié)果顯示注射病毒所引起的NLRP2表達(dá)下降可以減輕腦缺血所引起的IL-1β、IL-18、IL-6、TNF-α MCP-1等炎性因子表達(dá)升高。2.4 NLRP2對(duì)OGD誘導(dǎo)的原代星形膠質(zhì)細(xì)胞凋亡的影響流式結(jié)果顯示,對(duì)轉(zhuǎn)染si-NLRP2的星形膠質(zhì)細(xì)胞進(jìn)行OGD處理,凋亡的星形膠質(zhì)細(xì)胞明顯減少。3腦缺血損傷中NLRP2通路的調(diào)控作用WB結(jié)果顯示,小鼠腦缺血后,NLRP2、caspase-1、ASC、IL-1β等相關(guān)蛋白表達(dá)升高;注射攜帶NLRP2沉默基因的病毒小鼠,與注射空病毒的小鼠相比,NLRP2表達(dá)降低,而且注射攜帶NLRP2沉默基因的病毒小鼠所引起的NLRP2下降可以減輕腦缺血所引起的caspase-1、ASC、IL-1β等相關(guān)蛋白升高;培養(yǎng)原代星形膠質(zhì)細(xì)胞,WB結(jié)果顯示,轉(zhuǎn)入siRNA-NLRP2星形膠質(zhì)細(xì)胞NLRP2表達(dá)明顯降低。轉(zhuǎn)染siRNA-NLRP2的細(xì)胞所引起的NLRP2表達(dá)下降可以減輕OGD所引起的caspase-1,p-p65,IL-Iβ等相關(guān)蛋白表達(dá)升高。研究結(jié)論本實(shí)驗(yàn)首次證明了 NLRP2在腦缺血損傷中的表達(dá)變化,發(fā)現(xiàn)腦缺血損傷后NLRP2表達(dá)升高,進(jìn)一步導(dǎo)致caspase-1、ASC、IL-1β等相關(guān)蛋白升高,而NLRP2的缺失可以使腦梗死面積減少,腦缺血損傷得到改善,對(duì)于腦缺血具有一定的防治作用。
[Abstract]:In recent years, cerebral apoplexy is the main cause of long-term disability and death in the world, characterized by high morbidity, high mortality, high disability and high recurrence rate. Among them, ischemic stroke is more common than hemorrhagic stroke, with a proportion of more than 80%, which is due to obstruction of the brain artery to block the flow of blood to the brain. The pathophysiological process of ischemic cerebral apoplexy is complex and extensive, including oxidative stress, toxic effects of excitatory amino acids, energy metabolism disorders, changes in dynamic balance of cell ions, increased intracellular calcium levels, active oxygen mediated toxicity, and cytotoxic effects mediated by inflammatory cytokines. Recent studies have shown that the inflammatory response of the innate immune system is closely related to the process and progress of cerebral ischemia. The innate immune system is the first line of defense to restrict the undamaged host, and the intracellular and extracellular domain of the pattern recognition receptor (PRRs) can detect acute damage and initiate the inflammatory reaction. The oligomeric domain (NOD) - like receptor (NLRs) is a member of the intracellular pattern recognition receptor family and plays a key role in the inflammatory response. In the 22 category of human NLRs, 14 types include the thermal protein domain and form a NLRP subtype (NLRPs). In the NLRPs family, some members, such as NLRP1, NLRP3, and NLRP6, have been deeply studied, and they are available The recruitment of pro-caspase-1 through binding protein ASC activates the inflammatory corpuscles and activates the inactive pro-caspase-1 to mature caspase-1, resulting in the production and release of IL-1 beta and IL-18 and triggering the inflammatory reaction. And the role is rarely studied, especially in the central nervous system. Then whether NLRP2 is expressed in the central nervous system in the body and whether it is associated with cerebral ischemia, such as cerebral ischemia, is still needed to be further explored. In this experimental study, the model of the middle cerebral artery embolism (MCAO) and the glucose deprivation (OGD) model of the cultured cells were established. To explore the role and possible mechanism of NLRP2 in cerebral ischemia from two aspects in vivo and in vitro. Method 1 NLRP2 expression changes after cerebral ischemia in mice and the construction of cerebral ischemia model in 1.1 C57BL/6 wild type mice and neurology score 1.1.1 selected mice and construct ischemic model to select male wild type C57BL/6 experimental mice, weight 23g left Right, establish a middle cerebral artery embolism model. Neck median incision, incision of skin, separation of the left common carotid artery, internal carotid artery and external carotid artery under the microscope. The nylon thread plug is carefully inserted into the common carotid artery. When the cerebral blood flow meter detects the sudden drop of blood flow, it stops continuously and starts the time, after 12,24,48 hours, the mice are killed and taken to take mice fetch. Material.1.1.2 was used to evaluate the expression of NLRP2 in the brain of.1.2 after cerebral ischemia and its distribution and distribution of 1.2.1 using protein immunoblotting (Western blot, WB), Real-time PCR and immunohistochemistry (immunohistochemistry, IHC) for the detection of the changes in the expression of NLRP2 in the brain after cerebral ischemia. Immunofluorescence (IF) method for the detection of NLRP2 and the marker proteins of different cells in the brain of the mice, the distribution of NLRP2 in the brain, the construction of the.1.3 in vitro model and the detection of the original astrocytes by NLRP2 in vitro, and the establishment of oxygen deprivation (Oxygen Glucose Deprivation, OGD) model, respectively, for OGD. Treatment of 0.5,1,1.5,2h, Western blot (WB), tissue immunofluorescence (immunofluorescence, IF) and Real-time PCR detection of the expression of NLRP2 in the primary astrocytes after OGD;.2 NLRP2 in the brain ischemia injury in mice 2.1 injection of adeno-associated virus in mouse brain to use brain stereotaxis Injection of adeno-related virus vectors carrying NLRP2 silencing gene into specific parts of the nervous system by injection technique, the NLRP2 gene.2.2 injected into this site is injected into the brain of mice and the mice with NLRP2 silencing genes are injected into the brain. The brain of mice injected with NLRP2 silencing gene was stained with TTC, and the morphological damage was evaluated in.2.3 mice model of cerebral ischemia. CBA, Real-time PCR method was used to detect the level of pro-inflammatory factors in the brain homogenate of mice with NLRP2 silencing basis and.2. The effect of.4 NLRP2 on the apoptosis of primary astrocytes induced by OGD 2.4.1 the apoptosis of astrocytes transfected with 2.4.2 astrocytes, OGD treatment of astrocytes transfected with si-NLRP2, and the effect of Annexin V/PI staining on the apoptosis of primary astrocytes using flow cytometry to detect the apoptosis of astrocytes The regulation of NLRP2 pathway in.3 cerebral ischemia injury WB detection of NLRP2 effect on the level of Caspase-1, ASC, IL-1 beta in the brain of mice after cerebral ischemia The effect of NLRP2 on the expression of Caspase-1, p-p65, IL-1 beta in si-NLRP2 astrocytes after OGD treatment. Results 1 the expression of NLRP2 and its downstream molecules in the brain after cerebral ischemia in mice and the construction of the 1.1 C57BL/6 mouse model of cerebral ischemia and the neurology score were less than 2 in each group due to death or neurology score. The expression of NLRP2 in the brain of mice after.1.2 cerebral ischemia was removed and the distribution of NLRP2 in the brain of mice was removed and the distribution of 1.2.1 using protein immunoblotting (Western blot, WB), Real-time PCR and immunohistochemistry (immunohistochemistry, IHC) were used to detect the changes of NLRP2 expression after cerebral ischemia. We found that after cerebral ischemia, we found that the NLRP2 was after cerebral ischemia. The expression rose obviously and reached the peak in 24 hours. The results of immunohistochemical staining showed that.1.2.2 was mainly expressed in the primary astrocytes by immunofluorescence staining, and that NLRP2 was also expressed in the neurons. In the microglia, there was little expression of the expression of.1.3 in vitro model and the detection of NLRP2 in vitro. On behalf of astrocytes, the OGD model of oxygen deprivation was established. Through the analysis of WB and Real-time PCR, we found that the expression of NLRP2 increased significantly after OGD and reached the peak in OGD1.5 hours. The results of immunofluorescence showed that after the cell OGD1.5 hours, the expression of NLRP2 expression increased.2 NLRP2 in the cerebral ischemia injury of mice 2.1 injection of adeno-associated virus silencing. 4 weeks after the NLRP2 gene injection of the virus in the brain of mice, OCT was embedded in the brain tissue of mice. The scope of the virus infection was observed under the microscope under the microscope. The scope of the virus infection was larger, covering the.2.2 injection of the middle cerebral artery and the.2.2 virus with the NLRP2 silencing gene. After NLRP2 silencing gene cerebral ischemia, the neurology score of mice decreased obviously and the area of cerebral infarction decreased obviously. The detection of inflammatory factors in the.2.3 mice model of cerebral ischemia had cerebral ischemia treatment on mice injected with the virus and the virus injected with the NLRP2 silencing gene. The results of CBA and Real-time PCR showed the decline of NLRP2 expression caused by the injection virus. The effects of IL-1 beta, IL-18, IL-6, TNF- alpha MCP-1 and other inflammatory factors on the apoptosis of primary astrocytes induced by OGD can be alleviated by the flow cytometry results showed that the astrocytes transfected with si-NLRP2 were treated with OGD, and apoptotic astrocytes significantly reduced NLRP2 pathways in.3 cerebral ischemia. The WB results showed that the expression of NLRP2, caspase-1, ASC, IL-1 beta and other related proteins increased after cerebral ischemia in mice, and the mice injected with NLRP2 silencing genes decreased the NLRP2 expression compared with the mice injected with the empty virus, and the decrease of NLRP2 caused by the mice injected with the NLRP2 silent gene could reduce the cerebral ischemia. The associated proteins such as caspase-1, ASC, IL-1 beta and other related proteins were raised, and primary astrocytes were cultured. WB results showed that the expression of NLRP2 in siRNA-NLRP2 astrocytes decreased significantly. The decrease of NLRP2 expression caused by transfection of siRNA-NLRP2 cells could reduce caspase-1, p-p65, IL-I beta and other related proteins caused by OGD. This experiment is the first time to demonstrate the expression of NLRP2 in cerebral ischemia injury. It is found that the expression of NLRP2 increases after cerebral ischemia injury, which leads to the increase of Caspase-1, ASC, IL-1 beta and other related proteins, and the loss of NLRP2 can reduce the area of cerebral infarction and improve the cerebral ischemia injury, which has some preventive effect on cerebral ischemia.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R743

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