本文選題：錳 + 神經(jīng)毒性　； 參考：《第四軍醫(yī)大學(xué)》2016年博士論文

【摘要】：背景錳是人體所必須的微量元素。參與人體免疫反應(yīng),ATP的生成,骨骼生長(zhǎng)等生理反應(yīng)。此外,錳還可以作為機(jī)體許多酶的輔助因子,保障其發(fā)揮正常的生理作用。然而,當(dāng)機(jī)體攝入過(guò)多的錳則會(huì)引起錳中毒的發(fā)生,其臨床表現(xiàn)主要為類(lèi)似帕金森氏病病癥。中樞神經(jīng)系統(tǒng)是錳作用人體的主要靶器官,黑質(zhì)紋狀體通路更是錳損傷神經(jīng)系統(tǒng)的關(guān)鍵核團(tuán)。形成了錳能夠引起黑質(zhì)紋狀體內(nèi)多巴胺能神經(jīng)元功能減弱的經(jīng)典理論。隨著人們對(duì)錳神經(jīng)毒性的進(jìn)一步關(guān)注,錳對(duì)海馬腦區(qū)調(diào)控的空間記憶能力損傷也漸漸被人們所證實(shí)。研究證實(shí)錳在大腦中的蓄積所造成的神經(jīng)毒性作用與阿爾茲海默癥(Alzheimer’s disease,AD)、帕金森癥(Parkinson's disease,PD)、等多種神經(jīng)退行性疾病都有著密切的關(guān)系。在中樞神經(jīng)系統(tǒng)中,小膠質(zhì)細(xì)胞是免疫反應(yīng)的關(guān)鍵細(xì)胞,主要來(lái)源于腦膜,脈絡(luò)叢以及血管周?chē)�。其與巨噬細(xì)胞的功能相似,能通過(guò)一系列的模式識(shí)別受體(Pattern-Recognition Receptors,PRR)實(shí)時(shí)監(jiān)測(cè)中樞神經(jīng)系統(tǒng)的內(nèi)環(huán)境。當(dāng)組織受損或有害物質(zhì)入侵的情況下,小膠質(zhì)細(xì)胞發(fā)生活化反應(yīng),一方面發(fā)揮吞噬作用,一方面釋放大量炎癥因子,誘導(dǎo)外周固有免疫細(xì)胞及適應(yīng)性免疫細(xì)胞遷移至受損或入侵部位,發(fā)揮免疫防御作用。因此,小膠質(zhì)細(xì)胞活化及炎性因子釋放在中樞神經(jīng)系統(tǒng)的免疫應(yīng)答防御反應(yīng)中發(fā)揮了重要作用。小膠質(zhì)細(xì)胞活化后能夠快速誘導(dǎo)出多種炎性因子,其中包括白介素-1β(interleukin-1beta,il-1β)、腫瘤壞死因子-α(tumornecrosisfactor-alpha,tnf-α)和il-18等。本課題組以往研究發(fā)現(xiàn),錳暴露能夠誘導(dǎo)小膠質(zhì)細(xì)胞活化,活化后釋放的炎性因子可能是錳暴露導(dǎo)致神經(jīng)元損傷的關(guān)鍵因素,研究結(jié)果為錳神經(jīng)毒性機(jī)制闡明及錳中毒防護(hù)提供了重要線索。炎癥體是近年來(lái)炎性疾病領(lǐng)域關(guān)注的重點(diǎn),在炎性因子成熟、釋放過(guò)程中發(fā)揮重要作用。nlrp3炎癥體是調(diào)控il-1β、il-18等炎性因子成熟釋放的重要途徑。在神經(jīng)炎癥中,小膠質(zhì)細(xì)胞和巨噬細(xì)胞內(nèi)的nlrp3炎癥體能被β淀粉樣蛋白(amyloid-beta,aβ),α-共核蛋白(α-synuclein,α-syn)所激活�；罨膎lrp3發(fā)生寡聚化,募集接頭蛋白asc,通多card結(jié)構(gòu)域與pyd結(jié)構(gòu)域相互作用,進(jìn)一步激活caspase-1,進(jìn)而加工pro-il-1β為成熟的il-1β,并釋放于細(xì)胞外發(fā)揮作用。調(diào)控nlrp3炎癥體活化成熟的因素很多,細(xì)胞內(nèi)ros的增多、k+濃度改變、atp水平降低以及自噬等均能夠影響n(yōu)lrp3炎癥體的活化。自噬是細(xì)胞維持內(nèi)環(huán)境穩(wěn)定重要的生理過(guò)程。自噬的形成過(guò)程包括自噬的啟動(dòng)、延伸、與溶酶體的融合和降解幾個(gè)重要階段。當(dāng)自噬形成的某一過(guò)程受到抑制時(shí)則會(huì)導(dǎo)致自噬功能處于紊亂狀態(tài)。研究表明,許多神經(jīng)系統(tǒng)疾病的發(fā)生都與自噬功能的異常相關(guān),pd、ad等均發(fā)現(xiàn)體內(nèi)自噬降解過(guò)程異常。自噬與nlrp3炎癥體之間的關(guān)系較為復(fù)雜,一方面當(dāng)nlrp3炎癥體處于激活狀態(tài)時(shí),則會(huì)促進(jìn)自噬的發(fā)生;另一方面,自噬的過(guò)度活化則能夠抑制nlrp3炎癥體的活化。許多研究表明,自噬的抑制能夠活化nlrp3炎癥體,促進(jìn)pro-il-1β(36kda)向成熟il-1β轉(zhuǎn)變。雖然自噬能夠調(diào)控nlrp3炎癥體的活化,但其具體機(jī)制至今尚未闡明,這也成為當(dāng)今該領(lǐng)域研究的熱點(diǎn)和難點(diǎn)。目的研究錳暴露誘導(dǎo)的小膠質(zhì)細(xì)胞活化及其釋放的炎性因子在錳介導(dǎo)的學(xué)習(xí)記憶損傷中的作用;揭示nlrp3炎癥體活化是錳誘導(dǎo)小膠質(zhì)細(xì)胞活化釋放炎性因子il-1β和il-18的關(guān)鍵環(huán)節(jié);闡明自噬溶酶體功能紊亂與nlrp3炎癥體活化之間的關(guān)系;揭示錳暴露誘導(dǎo)的自噬功能紊亂調(diào)控nlrp3炎癥體活化的具體機(jī)制,為錳神經(jīng)毒性的防護(hù)和治療提供關(guān)鍵靶點(diǎn)和理論依據(jù)。方法1.通過(guò)皮下注射氯化錳的方法,構(gòu)建錳暴露的小鼠體內(nèi)模型,采用原子熒光光譜法檢測(cè)小鼠血錳和腦錳的濃度,運(yùn)用恐懼條件箱以及電生理實(shí)驗(yàn)評(píng)估小鼠錳暴露后學(xué)習(xí)和記憶能力的改變;2.通過(guò)免疫熒光化學(xué)法檢測(cè)錳暴露后nlrp3炎癥體在小鼠海馬區(qū)以及bv2細(xì)胞(之后簡(jiǎn)稱(chēng)為bv2)中的表達(dá)改變。westernblot檢測(cè)nlrp3炎癥體相關(guān)蛋白nlrp3、cleavedcaspase-1,炎性因子il-1β的表達(dá)改變;3.通過(guò)elisa檢測(cè)錳暴露后炎性因子il-1β、il-18和tnf-α的改變,以及qrt-pcr檢測(cè)nlrp3和炎性因子il-1β、il-18mrna水平的改變。4.通過(guò)免疫熒光化學(xué)法檢測(cè)自噬相關(guān)蛋白lc3的表達(dá)影響,westernblot檢測(cè)自噬相關(guān)蛋白beclin1、atg5、lc3、p62、組織蛋白酶b(cathepsinb)蛋白的變化。透射電鏡觀察bv2自噬亞細(xì)胞結(jié)構(gòu)的改變;,5.分別運(yùn)用atg5sirna、bafa1以及nh4cl處理bv2,westernblot檢測(cè)錳暴露后nlrp3炎癥體相關(guān)蛋白nlrp3、cleavedcaspase-1,炎性因子il-1β的表達(dá)改變,elisa檢測(cè)錳暴露后炎性因子il-1β、il-18的改變。結(jié)果1.皮下注射氯化錳7天后,小鼠血錳和腦錳與對(duì)照組相比明顯升高,恐懼條件箱檢測(cè)以及l(fā)tp實(shí)驗(yàn)發(fā)現(xiàn)錳暴露后能夠引起小鼠學(xué)習(xí)記憶能力下降;2.海馬腦片以及bv2免疫熒光化學(xué)染色表明,錳暴露能夠引起nlrp3炎癥體表達(dá)增多。westernblot結(jié)果顯示,體內(nèi)外錳暴露均能夠引起nlrp3炎癥體相關(guān)蛋白nlrp3、cleavedcaspase-1表達(dá)的增加;3.elisa實(shí)驗(yàn)檢測(cè)發(fā)現(xiàn)錳暴露能夠誘導(dǎo)炎性因子il-1β、il-18表達(dá)增加,并且在mrna水平檢測(cè)上也得以證實(shí);4.免疫細(xì)胞化學(xué)熒光染色結(jié)果提示,錳暴露可導(dǎo)致bv2內(nèi)lc3標(biāo)記的自噬體大量聚集。westernblot發(fā)現(xiàn)與對(duì)照組相比,錳暴露后自噬體相關(guān)蛋白beclin1、atg5、lc3ii、p62、組織蛋白酶bbiao’da表達(dá)顯著增加。p62升高提示錳暴露能夠引起自噬溶酶體降解功能出現(xiàn)障礙。組織蛋白酶b的表達(dá)增加以及電鏡檢測(cè)所發(fā)現(xiàn)的溶酶體形態(tài)異常提示錳暴露能夠引起bv2溶酶體功能異常。5.Atg5 siRNA和Baf A1分別抑制自噬體的啟動(dòng)、延伸和與溶酶體的融合后,并不能抑制錳暴露所誘導(dǎo)的NLRP3炎癥體的活化及IL-1β、IL-18的釋放。NH4Cl作用BV2后,Western blot檢測(cè)發(fā)現(xiàn)其能夠降低組織蛋白酶B的表達(dá),抑制錳暴露所誘導(dǎo)的NLRP3炎癥體的活化以及炎性因子IL-1β、IL-18的釋放。結(jié)論1.體內(nèi)實(shí)驗(yàn)證實(shí)錳能夠降低海馬腦區(qū)所調(diào)控的學(xué)習(xí)和記憶能力。2.錳暴露對(duì)學(xué)習(xí)記憶能力的影響可能與其所誘導(dǎo)的小膠質(zhì)細(xì)胞活化后釋放的促炎性因子(IL-1β和IL-18等)有關(guān)。3.錳暴露激活NLRP3炎癥體通路是其介導(dǎo)炎性因子釋放的關(guān)鍵因素。4.自噬溶酶體功能紊亂參與了錳誘導(dǎo)的NLRP3炎癥體活化,自噬體啟動(dòng)、延伸及與溶酶體融合的異常不是調(diào)控NLRP3炎癥體活化的重要環(huán)節(jié).5.錳暴露導(dǎo)致的溶酶體功能異常及cathepsin B的釋放是引起NLRP3炎癥體活化的關(guān)鍵因素。
[Abstract]:Background manganese is a necessary trace element in human body. It participates in human immune response, ATP formation, bone growth and other physiological responses. In addition, manganese can also be used as an auxiliary factor for many enzymes in the body to ensure its normal physiological function. However, excessive manganese intake may lead to the occurrence of manganese poisoning, and its clinical manifestations are mainly similar. Parkinson's disease. The central nervous system is the main target organ of manganese in the human body, and the nigrostriatal pathway is the key nucleus of the manganese damaged nervous system. The classical theory that manganese can cause the dysfunction of dopaminergic neurons in the substantia nigra is a classic theory. With the further attention to the toxicity of manganese, manganese has been used in the hippocampus The neurotoxicity of manganese in the brain has been confirmed. The neurotoxicity of manganese in the brain is closely related to Alzheimer 's disease (AD), Parkinson's disease (PD), and other neurodegenerative diseases. In the central nervous system, small glue is found. The cell is the key cell of the immune response, mainly from the meninges, choroid plexus, and around the blood vessels. It is similar to the function of macrophages and can monitor the internal environment of the central nervous system in real time through a series of pattern recognition receptors (Pattern-Recognition Receptors, PRR). On the one hand, the cell acts as a phagocytosis. On the one hand, it releases a large number of inflammatory factors, and induces the migration of immune cells and adaptive immune cells to the damaged or invasive sites, and plays an immune defense role. Therefore, the activation of microglia and inflammatory factors are released in the immune response defense response of the central nervous system. A variety of inflammatory factors can be induced quickly after the activation of microglia, including -1 beta (interleukin-1beta, IL-1 beta), tumor necrosis factor - alpha (tumornecrosisfactor-alpha, tnf- alpha), and IL-18, etc. this group has previously found that manganese exposure can induce microglia activation and release after activation. Inflammatory factors may be the key factors of neuronal damage caused by manganese exposure. The results provide an important clue to the clarification of manganese neurotoxicity and the protection of manganese poisoning. The inflammatory body is the focus of attention in the field of inflammatory diseases in recent years. The inflammatory factors are mature and play an important role in the release process. The.Nlrp3 inflammatory body is the regulation of IL-1 beta, IL-18 and so on. An important route to mature release of inflammatory factors. In neuropathy, NLRP3 inflammation in microglia and macrophages can be activated by beta amyloid (amyloid-beta, a beta), alpha -synuclein (alpha -synuclein, alpha -syn). Activated NLRP3 oligomerization, recruitment of the head protein ASC, and the interaction of the multi card domain with the PYD domain. One step activates caspase-1, and then processes pro-il-1 beta as the mature IL-1 beta and releases it out of the cell. There are many factors regulating the activation of the NLRP3 inflammatory body, the increase of ROS in the cell, the change of k+ concentration, the decrease of ATP level and autophagy, which can affect the activation of NLRP3 inflammatory body. Autophagy is an important source of the cell maintenance of the internal stability. Process. The process of autophagy consists of the initiation, extension, fusion and degradation of the lysosomes. The autophagy is in disorder when a certain process of autophagy is inhibited. The study shows that the occurrence of many nervous system diseases is associated with autophagic function, PD, ad and so on. The process of autophagic degradation is abnormal. The relationship between autophagy and NLRP3 inflammatory body is more complex. On one hand, when the NLRP3 inflammatory body is activated, autophagy can be promoted; on the other hand, the excessive activation of autophagy can inhibit the activation of the NLRP3 inflammatory body. Many studies have shown that the inhibition of autophagy can activate the NLRP3 inflammatory body and promote the pro- IL-1 beta (36kDa) changes to mature IL-1 beta. Although autophagy can regulate the activation of NLRP3 inflammatory body, its specific mechanism has not yet been elucidated. This has also become a hot and difficult point in this field. The activation of NLRP3 inflammatory body is a key link in the activation and release of inflammatory factors IL-1 beta and IL-18 by manganese induced microglia, and clarifies the relationship between the dysfunction of autophagic lysosome and the activation of NLRP3 inflammatory body, and reveals the body mechanism of the regulation of the dysfunction of autophagy induced by manganese exposure, which regulates the activation of NLRP3 inflammatory bodies, and provides the protection and treatment of manganese neurotoxicity. For the key target and theoretical basis. Method 1. the model of manganese exposed mice was constructed by subcutaneous injection of manganese chloride. The concentration of manganese and manganese in mice was detected by atomic fluorescence spectrometry. The changes of learning and memory ability of mice after manganese exposure were evaluated by using the fear condition box and electrophysiological experiments. 2. by immunofluorescence. The expression changes of NLRP3 inflammatory body in the hippocampus and BV2 cells (later called BV2) after manganese exposure were detected by.Westernblot to detect the changes in the expression of NLRP3 inflammatory proteins NLRP3, cleavedcaspase-1, and inflammatory factor IL-1 beta; 3. the changes of IL-1 beta, IL-18 and tnf- alpha after manganese exposure were detected by ELISA, and the changes in IL-18 and tnf- alpha were detected by ELISA. Detection of NLRP3 and inflammatory factor IL-1 beta, il-18mrna level changes.4. by immunofluorescence chemical assay of autophagy related protein LC3 expression effect, Westernblot detection of autophagy related proteins Beclin1, ATG5, LC3, p62, cathepsin B (CathepsinB) protein changes. Transmission electromicroscope observation of autophagy subcellular structure changes; 5. G5sirna, bafa1 and NH4Cl treated BV2, Westernblot detected the expression of NLRP3 inflammatory body associated protein NLRP3, cleavedcaspase-1, and inflammatory factor IL-1 beta after manganese exposure. ELISA detected the IL-1 beta and IL-18 changes after manganese exposure. Results 1. after 7 days of subcutaneous injection of manganese chloride, the blood manganese and brain manganese in mice were significantly higher than those of the control group. Condition box test and LTP experiment found that manganese exposure could cause the decrease of learning and memory ability in mice. 2. hippocampal slices and BV2 immunofluorescence staining showed that manganese exposure could cause increased expression of NLRP3 inflammatory body.Westernblot, and manganese exposure in vivo and in vivo could lead to NLRP3 inflammation related protein NLRP3, cleavedcaspase-1 3.elisa test found that manganese exposure could induce inflammatory factors IL-1 beta, IL-18 expression increased, and confirmed on mRNA level detection; 4. immunocytochemical fluorescence staining showed that manganese exposure could lead to a large amount of.Westernblot in the autophagic body of LC3 labeled BV2 within BV2 and the manganese exposure was compared with the control group. The expression of phagocytic related proteins Beclin1, ATG5, lc3ii, p62, cathepsin bbiao 'Da expressed a significant increase in.P62, suggesting that manganese exposure can cause the dysfunction of autophagic lysosome degradation. The increase in the expression of cathepsin B and the abnormalities of lysosome morphology found by electron microscopy detection suggest that manganese exposure can cause BV2 lysosome dysfunction.5.At. G5 siRNA and Baf A1 inhibit the activation of autophagosomes, extending and merging with lysosomes, which do not inhibit the activation of NLRP3 inflammatory bodies induced by manganese exposure and IL-1 beta. After the release of.NH4Cl in IL-18, Western blot detection found that the Western blot can reduce the expression of cathepsin B, and inhibit the activation of inflammatory bodies induced by manganese exposure. And the release of inflammatory factors IL-1 beta, IL-18. Conclusion 1. in vivo real manganese can reduce the learning and memory ability of the hippocampus, the effects of.2. manganese exposure on learning and memory ability may be related to the proinflammatory factors (IL-1 beta and IL-18, etc.) released by the induced microglia activation (IL-1 beta and IL-18, etc.), which are related to the activation of NLRP3 inflammation by.3. manganese exposure. The pathway is a key factor in the release of inflammatory factors,.4. autophagic lysosome dysfunction participates in the activation of manganese induced NLRP3 inflammatory bodies, autophagosome initiation, extension, and the abnormality of fusion with lysosomes are not important links to regulate the activation of NLRP3 inflammatory bodies. The dysfunction of the lysosome caused by.5. manganese exposure and the release of cathepsin B is the cause of NLR The key factor in the activation of P3 inflammatory body.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R135.1

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