發(fā)布時(shí)間：2018-01-04 23:19

  本文關(guān)鍵詞：NLRP3介導(dǎo)的神經(jīng)炎癥反應(yīng)在顱腦創(chuàng)傷中的作用及機(jī)制研究　出處：《南京醫(yī)科大學(xué)》2017年博士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： 顱腦外傷 炎癥反應(yīng) NLRP3炎癥小體 線粒體自噬 omega-3

【摘要】：第一部分線粒體自噬對(duì)顱腦外傷后神經(jīng)炎癥反應(yīng)和神經(jīng)元凋亡的調(diào)控作用目的:研究顱腦外傷后線粒體自噬的發(fā)生情況和具體機(jī)制,探討其和神經(jīng)炎癥反應(yīng)之間的關(guān)系。方法:運(yùn)用臨床標(biāo)本,以癲癇患者的腦組織為對(duì)照組,通過(guò)電鏡和western blotting等方法檢測(cè)顱腦損傷后腦組織的自噬及線粒體自噬發(fā)生情況;以WT和GFP-LC3轉(zhuǎn)基因Sprague Dawley老鼠為研究對(duì)象,運(yùn)用控制性皮層損傷方法,構(gòu)建顱腦損傷的動(dòng)物模型;通過(guò)免疫熒光、western blotting、電鏡等檢測(cè)線粒體自噬的發(fā)生情況;使用BAF和3-MA兩種不同的自噬抑制劑,檢測(cè)其對(duì)顱腦外傷后線粒體自噬的影響;依據(jù)外傷后1、3、6以及24小時(shí),取腦組織檢測(cè)線粒體自噬和線粒體釋放Cyt C的情況,研究線粒體自噬和細(xì)胞死亡在時(shí)間上的關(guān)系;檢測(cè)正常狀態(tài)下和顱腦外傷后心磷脂在線粒體上的分布情況;抑制PLS3或者CLS,干擾心磷脂的重新分布,檢測(cè)其對(duì)顱腦外傷后線粒體自噬的影響;使用線粒體自噬抑制劑mdivi-1,Sprague Dawley大鼠分為sham組,TBI組和TBI+mdivi-1組;TUNEL和western blotting檢測(cè)損傷后細(xì)胞凋亡情況;腦缺損面積實(shí)驗(yàn),檢測(cè)腦組織損傷情況;平衡木實(shí)驗(yàn)和水迷宮實(shí)驗(yàn),探討外傷后神經(jīng)功能恢復(fù)情況。結(jié)果:1,電鏡顯示顱腦外傷后大量損傷的線粒體被雙層膜包裹,提示顯著增加的線粒體自噬;2,western blotting顯示自噬的標(biāo)志蛋白LC3-Ⅱ明顯升高,p62下降,線粒體的標(biāo)志蛋白(COXIV,MnSOD,TOM40)下降;3,免疫熒光顯示GFP-LC3和線粒體共定位明顯增加;4,線粒體自噬發(fā)生早于Cytc從損傷線粒體釋放;5,心磷脂由線粒體內(nèi)膜翻轉(zhuǎn)至外膜,與LC3結(jié)合,阻止心磷脂外翻,抑制顱腦外傷后線粒體自噬;6,抑制線粒體自噬加劇顱腦損傷后神經(jīng)炎癥反應(yīng);7,抑制線粒體自噬使腦缺損面積增加;8,干擾大鼠神經(jīng)功能恢復(fù),影響平衡木實(shí)驗(yàn)和水迷宮實(shí)驗(yàn)。結(jié)論:1,顱腦損傷后,腦組織線粒體自噬顯著增加;2,線粒體自噬早于細(xì)胞凋亡的發(fā)生;3,心磷脂充當(dāng)識(shí)別損傷線粒體的作用,調(diào)節(jié)線粒體自噬;4,線粒體自噬起神經(jīng)保護(hù)作用,抑制線粒體自噬會(huì)加劇神經(jīng)炎癥反應(yīng),阻礙神經(jīng)功能恢復(fù)。第二部分NLRP3炎癥小體在顱腦外傷中的重要作用目的:研究顱腦外傷后神經(jīng)炎癥反應(yīng)的發(fā)生情況,探討NLRP3在其中的重要調(diào)節(jié)作用,及與預(yù)后的關(guān)系。方法:運(yùn)用臨床標(biāo)本,以癲癇患者的腦組織為對(duì)照組,通過(guò)免疫組化和western blotting等方法檢測(cè)顱腦損傷后腦組織的神經(jīng)炎癥發(fā)生情況;運(yùn)用siRNA敲低NLRP3后,western blotting檢測(cè)敲低效果,研究其對(duì)顱腦外傷后神經(jīng)炎癥反應(yīng)的影響;以WT、及NLRP3-/-caspase-1-/-、IL-1R-/-轉(zhuǎn)基因小鼠為研究對(duì)象,構(gòu)建控制性皮層損傷模型,平衡木實(shí)驗(yàn)和水迷宮實(shí)驗(yàn),探討顱腦外傷后肌力、運(yùn)動(dòng)、學(xué)習(xí)、記憶、認(rèn)知等神經(jīng)功能恢復(fù)情況。結(jié)果:1,免疫組化顯示顱腦外傷后NLRP3、IL-1β和IL-18表達(dá)增加,提示顯著增強(qiáng)的神經(jīng)炎癥反應(yīng);2,western blotting結(jié)果顯示caspase-1(P20)和分泌型IL-1β明顯增加;3,運(yùn)行siRNA敲低nlrp3,使nlrp3低表達(dá),后續(xù)western blotting結(jié)果顯示caspase-1(P20)和IL-1β明顯減少;4,在平衡木實(shí)驗(yàn)和水迷宮實(shí)驗(yàn)中,與WT小鼠相比,NLRP3-/-caspase-1-/-、IL-1R-/-轉(zhuǎn)基因小鼠的外傷后神經(jīng)功能恢復(fù)更好。結(jié)論:1,顱腦損傷后,NLRP3表達(dá)增加,神經(jīng)炎癥反應(yīng)明顯增強(qiáng);2,敲低NLRP3,顯著減少顱腦外傷引起的神經(jīng)炎癥反應(yīng);3,敲除NLRP3,或者caspase-1,或者IL-1R有利于顱腦外傷后神經(jīng)功能恢復(fù)。第三部分Omega-3通過(guò)調(diào)節(jié)NLRP3介導(dǎo)的炎癥反應(yīng)減少顱腦外傷后細(xì)胞死亡和改善預(yù)后目的:探討omega-3如何抑制顱腦外傷后神經(jīng)炎癥反應(yīng),及改善顱腦損傷后神經(jīng)功能缺陷。方法:合籠后第1天,雌鼠被隨機(jī)分配接受標(biāo)準(zhǔn)食物(EPA 20:5 n-3 0.02%和DHA22:6 n-3 0.02%),或高 co-3 Fas 的飲食(EPA5.3%和 DHA23.8%),或者高ω-6 Fas 的飲食;術(shù)前 6 周予以 co-3(DHA,22:6,#D2534),或者 ω-6(oleic acid,18:2,#62160),或者 ω-9(linolenic acid,18:1,#01008),或者生理鹽水灌胃,2 次/周;通過(guò)ELISA、western blotting等檢測(cè)不同組的顱腦外傷后神經(jīng)炎癥反應(yīng);使用GPR40受體拮抗劑GW1100或者siRNAGPR40,抑制ω-3 Fas的抗炎的作用;通過(guò)免疫共沉淀檢測(cè)ARRB2與NLRP3結(jié)合情況;分離線粒體和胞漿蛋白,檢測(cè)NLRP3和線粒體共定位情況;TNUNEL檢測(cè)顱腦外傷后細(xì)胞死亡情況,同時(shí)使用western blotting檢測(cè)cleaved-caspase-3表達(dá)水平;使用腦水腫實(shí)驗(yàn)和腦缺損面積,檢測(cè)腦損傷情況;使用平衡木實(shí)驗(yàn)和水迷宮實(shí)驗(yàn)探討外傷后神經(jīng)功能恢復(fù)情況。結(jié)果:1,與sham組相比,ELISA結(jié)果顯示co-3Fas抑制顱腦外傷誘導(dǎo)的IL-1β、IL-18 和 IL-6;2,omega-6 或-9 不能抑制 caspase-1 和 IL-1β的激活;3,siRNA GPR40或者GW1100能夠顯著抑制ω-3Fas的抵抗炎癥作用;4,免疫共沉淀結(jié)果顯示ω-3Fas促進(jìn)GPR40下游蛋白ARRB2與NLRP3相結(jié)合;5,分離線粒體蛋白和胞漿蛋白,后續(xù)western blotting結(jié)果顯示ω-3Fas抑制NLRP3與損傷的線粒體結(jié)合,從而減少cleaved-caspase-1和IL-1β的表達(dá);6,ω-3Fas可顯著減少顱腦外傷引起的細(xì)胞死亡;7,ω-3Fas減少顱腦外傷引起的皮層缺損和腦水腫,促進(jìn)運(yùn)動(dòng)和認(rèn)知能給恢復(fù);8,GW1100抑制ω-3Fas對(duì)于顱腦外傷的神經(jīng)保護(hù)作用。結(jié)論:1,ω-3Fas改善腦外傷引起的神經(jīng)炎癥反應(yīng)和神經(jīng)功能行為缺陷;2,ω-3Fas通過(guò)GPR40促進(jìn)ARRB2與NLRP3相結(jié)合,并抑制NLRP3與損傷的線粒體結(jié)合,從而減少創(chuàng)傷性神經(jīng)炎癥反應(yīng);3,ω-3Fas通過(guò)GPR40/ARRB2/NLRP3信號(hào)通路有效減輕腦水腫和腦皮層缺損,促進(jìn)顱腦外傷后神經(jīng)功能恢復(fù)。
[Abstract]:The first part of the regulation of mitochondrial autophagy and apoptosis of nerve inflammation after traumatic brain injury Objective: the occurrence and the specific mechanism of mitochondrial autophagy after traumatic brain injury, to investigate the relationship between inflammatory reaction and nerve. Methods: the clinical specimens in the brain of epileptic patients as the control group, the incidence of brain tissue by electron microscopy western and blotting were used to detect brain injury and mitochondrial autophagy autophagy; WT and Sprague Dawley in GFP-LC3 transgenic mice as the research object, using the control method of cortical injury, animal model of brain injury; by immunofluorescence, Western blotting, electron microscopy detection of mitochondrial autophagy occurs; the use of BAF and 3-MA in two different autophagy inhibitor, testing its impact on mitochondrial autophagy after traumatic brain injury; on the basis of 1,3,6 and 24 hours after injury, brain tissue Detection of mitochondrial autophagy and mitochondrial release of Cyt and C, to study the relationship between mitochondrial autophagy and cell death in time; the distribution of cardiolipin in mitochondrial detection on normal condition and after traumatic brain injury; inhibition of PLS3 or CLS, the redistribution of interference of cardiolipin, testing its effect on mitochondrial autophagy after traumatic brain injury; the use of mitochondrial autophagy inhibitor mdivi-1, Sprague Dawley rats were divided into sham group, TBI group and TBI+mdivi-1 group; TUNEL and Western blotting to detect cell apoptosis after brain injury; defect detection experiments, damage of brain tissue; the balance beam test and water maze test, to study the recovery of nerve function after injury. Results: 1. Electron microscopy showed that large amounts of damage to mitochondria after brain trauma was encapsulated in a double membrane, suggesting that mitochondrial autophagy significantly increased; 2, Western blotting LC3- II protein markers of autophagy increased significantly High p62 decreased mitochondrial protein markers (COXIV, MnSOD, TOM40) decreased; 3, immunofluorescence showed GFP-LC3 and mitochondrial colocalization increased significantly; 4, mitochondrial autophagy occurred earlier than Cytc from the mitochondrial release; 5, mitochondrial cardiolipin by turning to the outer membrane, combined with LC3, preventing cardiolipin valgus inhibition of mitochondrial autophagy after traumatic brain injury; 6, inhibition of mitochondrial autophagy exacerbated brain nerve injury in inflammatory reaction; 7, inhibition of mitochondrial autophagy enables the brain defect area increased; 8, the interference effect of neural functional recovery of rats, beam balance test and water maze test. Conclusion: 1, brain injury, brain mitochondrial autophagy significantly increased; in the early 2, mitochondrial autophagy apoptosis; 3, cardiolipin acts as the damage identification of the role of mitochondria in regulating mitochondrial autophagy; 4, mitochondrial autophagy plays a role in neuroprotection, inhibition of mitochondrial autophagy exacerbates neuroinflammation, Hinder the recovery of nerve function. The second part of the important role of NLRP3 inflammasome in Brain Injury Objective: incidence of nerve inflammation after traumatic brain injury research of NLRP3, in which an important role, and the relationship with prognosis. Methods: the clinical specimens in epileptic patients with brain tissue as the control group, the incidence of nerve inflammation through brain tissue by immunohistochemistry and Western blotting methods to detect brain injury; using siRNA knockdown NLRP3, Western detection of blotting knockdown effect, to study its effect on nerve inflammation after traumatic brain injury; WT, and NLRP3-/-caspase-1-/-, IL-1R-/- transgenic mice as the research object, the construction control of cortex injury model. Balance beam test and water maze test, to investigate the brain injury after muscle strength, exercise, learning, memory, cognitive and neural functional recovery. Results: 1. Immunohistochemistry showed that the skull After traumatic brain injury NLRP3, IL-1 beta and IL-18 increase the expression of nerve inflammation prompted significantly enhanced; 2, Western blotting results showed that caspase-1 (P20) and secretory IL-1 beta increased significantly; 3, run siRNA knockdown of NLRP3, the low expression of NLRP3, the subsequent Western blotting results showed caspase-1 (P20) and IL-1 beta in 4, significantly reduced; the balance beam test and water maze test, compared with WT mice, NLRP3-/-caspase-1-/-, better functional recovery in IL-1R-/- transgenic mice after injury. Conclusion: 1, after craniocerebral injury, increase the expression of NLRP3, inflammatory reaction was enhanced obviously; 2, knockdown of NLRP3 significantly reduced brain injury of nerve inflammation by 3; knockdown of NLRP3 or caspase-1, or IL-1R, is conducive to the recovery of nerve function after traumatic brain injury. The third part Omega-3 to reduce the inflammatory reaction by regulating brain injury after NLRP3 mediated cell death and improve the prognosis of objective Study how to suppress the inflammatory response of omega-3 nerve after traumatic brain injury, and improve the defect of nerve function after brain injury. Methods: first days after mating, female rats were randomly assigned to receive standard food (EPA 20:5 n-3 0.02% and DHA22:6 n-3 0.02%, co-3) or high Fas diet (EPA5.3% and DHA23.8%), or high Omega -6 the Fas diet; 6 weeks before surgery to be co-3 (DHA, 22:6, #D2534), or -6 (oleic acid, w 18:2, #62160), or -9 (linolenic acid, w 18:1, #01008), or saline, 2 times per week; through ELISA, nerve inflammation brain injury Western blotting detection of different groups; the use of GPR40 receptor antagonists GW1100 or siRNAGPR40 inhibited Omega -3 Fas anti-inflammatory effect; by immunoprecipitation assay of ARRB2 and NLRP3 combination; separation of cytosolic and mitochondrial proteins, the detection of NLRP3 and mitochondria co localization; TNUNEL detection after craniocerebral trauma Cell death, while using Western blotting to detect cleaved-caspase-3 expression level; brain edema and brain defects using experimental area to detect brain injury; use the balance test and water maze test to investigate the recovery of nerve function after injury. Results: 1, compared with the sham group, ELISA results showed that co-3Fas inhibited brain injury induced by IL-1 beta. IL-18 and IL-6; 2, the activation of omega-6 or -9 could not inhibit caspase-1 and IL-1 beta; 3, GPR40 or GW1100 siRNA resist inflammation can significantly inhibit -3Fas; 4, results showed that Omega -3Fas promotes GPR40 downstream protein ARRB2 and NLRP3 combined immunoprecipitation; 5, separation of mitochondrial and cytoplasmic protein, follow-up western blotting results showed that -3Fas inhibited NLRP3 and Omega damage mitochondrial binding thereby reducing the expression of cleaved-caspase-1 and IL-1 beta; 6, Omega -3Fas can significantly reduce brain injury caused by Cell death; 7, Omega -3Fas reduce craniocerebral trauma caused by the cortical defect and brain edema, promote the movement and cognition to recovery; 8, GW1100 inhibited the Omega -3Fas protective effect on nerve craniocerebral injury. Conclusion: 1, nerve inflammation and nerve function Omega -3Fas caused by traumatic brain injury can improve the behavior of defects; 2. -3Fas through the promotion of GPR40 ARRB2 combined with NLRP3, and inhibit the binding of NLRP3 and the damage of mitochondria, thereby reducing traumatic nerve inflammation; 3, Omega -3Fas via GPR40/ARRB2/NLRP3 pathway effectively reduce brain edema and cerebral cortex defect, promote the recovery of neurological function after cerebral trauma.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R651.15

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