發(fā)布時(shí)間：2018-07-03 21:40

  本文選題：骨癌 + 痛覺(jué)過(guò)敏��； 參考：《蘇州大學(xué)》2016年博士論文

【摘要】：原發(fā)性骨腫瘤或轉(zhuǎn)移性腫瘤導(dǎo)致的骨癌痛是一種嚴(yán)重且頑固性疼痛,嚴(yán)重影響或損害了病人的功能狀態(tài),生活質(zhì)量以及生存時(shí)間。目前,對(duì)骨疼痛的分子機(jī)制還是不明確,有效的臨床治療手段有限。因此,迫切需進(jìn)一步探索骨癌痛發(fā)生發(fā)展的分子機(jī)制,以尋找新的治療靶點(diǎn)。近年來(lái)的研究發(fā)現(xiàn)腫瘤對(duì)骨質(zhì)的破壞以及酸中毒導(dǎo)致的炎癥發(fā)生,腫瘤釋放的產(chǎn)物,還有腫瘤引起的骨折、局部缺血、腫瘤入侵等導(dǎo)致的神經(jīng)纖維損傷都可能是引起骨癌痛的原因。有不少研究報(bào)導(dǎo)嘌呤能受體P2X3R在炎性痛、神經(jīng)病理性疼痛和內(nèi)臟痛的發(fā)生發(fā)展中發(fā)揮著重要作用,但對(duì)其在骨癌痛中作用功能及其表達(dá)調(diào)控機(jī)制研究甚少。而在骨癌痛形成過(guò)程中,腫瘤細(xì)胞及基質(zhì)細(xì)胞會(huì)分泌些促炎相關(guān)因子來(lái)敏化外周初級(jí)傳入神經(jīng)元,引起神經(jīng)元中炎癥相關(guān)因子表達(dá)升高,其中NF-κB作為一種重要炎癥相關(guān)調(diào)控因子,廣泛參與炎癥,疼痛相關(guān)基因表達(dá)調(diào)控,但在骨癌痛形成過(guò)程中NF-κB是否參與調(diào)控P2X3R的表達(dá)仍然不清,因此,我們將從表觀遺傳的角度探討P2X3R的調(diào)控特征及其N(xiāo)F-κB的作用特點(diǎn),以尋求治療骨癌痛的新靶點(diǎn),為臨床治療骨癌痛提供理論依據(jù)。第一部分:研究P2X3R和NF-κB是否參與骨癌痛的發(fā)生發(fā)展1.研究目的(1)檢測(cè)骨癌模型大鼠是否存在痛覺(jué)過(guò)敏及其相關(guān)電生理機(jī)制;(2)研究P2X3R是否參與骨癌痛的發(fā)生發(fā)展;(3)探討NF-κB介導(dǎo)大鼠骨癌痛的作用機(jī)制。2.實(shí)驗(yàn)方法(1)實(shí)驗(yàn)研究對(duì)象為雌性成年SD大鼠。通過(guò)將大鼠乳腺癌Walker 256細(xì)胞(4×105個(gè))注射到脛骨的骨髓腔內(nèi)來(lái)建立骨癌痛大鼠模型。應(yīng)用X射線(xiàn)成像及組織形態(tài)學(xué)方法檢測(cè)脛骨形態(tài)學(xué)變化以驗(yàn)證模型建立是否成功,用von Frey filament(VFF)和熱刺激儀分別檢測(cè)機(jī)械痛閾和熱痛閾,以及雙足平衡儀檢測(cè)雙足平衡差異來(lái)評(píng)價(jià)骨癌誘導(dǎo)的痛覺(jué)過(guò)敏;(2)用Di I逆行示蹤劑標(biāo)記支配大鼠脛骨特異性DRG神經(jīng)元;(3)用Real-time PCR和Western blotting方法檢測(cè)大鼠脛骨相關(guān)的DRG中NF-κB家族成員Rel B,p52,p65 p-p65和RANKL,以及嘌呤受體P2X3R,P2X1R,P2X2R,CBS(硫化氫合成酶)的表達(dá)情況;(4)用全細(xì)胞膜片鉗技術(shù)檢測(cè)支配大鼠脛骨特異性DRG神經(jīng)元的ATP電流;(5)檢測(cè)嘌呤能受體抑制劑Suramin或P2X3R和P2X2/3R強(qiáng)效抑制劑A317491能否翻轉(zhuǎn)骨癌大鼠痛敏來(lái)確定P2X3R是否參與骨癌痛的發(fā)生;(6)檢測(cè)p65抑制劑PDTC或BAY-11-7082能否翻轉(zhuǎn)骨癌大鼠痛敏來(lái)確定p65是否參與骨癌痛形成;(7)檢測(cè)鞘內(nèi)注射p65 sh RNA慢病毒是否降低脛骨特異性神經(jīng)元興奮性和骨癌痛敏行為,進(jìn)一步確定p65是否參與骨癌痛的形成。3.實(shí)驗(yàn)結(jié)果(1)乳腺癌細(xì)胞注射兩周后X射線(xiàn)成像和形態(tài)學(xué)觀察到骨癌大鼠脛骨骨質(zhì)發(fā)生明顯破壞,脛骨骨髓腔中充滿(mǎn)大量癌細(xì)胞;行為學(xué)檢測(cè)顯示骨癌大鼠出現(xiàn)明顯的痛覺(jué)過(guò)敏;(2)熒光逆行示蹤劑Di I標(biāo)記的支配大鼠脛骨特異性神經(jīng)元主要分布在腰段L2-L5這4個(gè)節(jié)段的DRG中;(3)電生理學(xué)檢測(cè)發(fā)現(xiàn),與對(duì)照組相比,腫瘤細(xì)胞注射兩周后,骨癌大鼠脛骨特異性DRG神經(jīng)元的ATP電流顯著增強(qiáng),ATP誘發(fā)的動(dòng)作電位個(gè)數(shù)也顯著增加;(4)癌細(xì)胞注射兩周后大鼠脛骨相關(guān)的DRG中P2X3R表達(dá)顯著上調(diào)。鞘內(nèi)分別注射嘌呤能受體抑制劑Suramin,P2X3R和P2X2/3R強(qiáng)效抑制劑A317491能顯著緩解骨癌大鼠的痛覺(jué)過(guò)敏,效果呈時(shí)間和劑量依賴(lài)性;(5)癌細(xì)胞注射兩周后顯著增加大鼠脛骨相關(guān)的DRG中p65及磷酸化p65的表達(dá),用p65抑制劑PDTC或BAY-11-7082能顯著減輕骨癌大鼠的痛覺(jué)過(guò)敏,緩解效果呈現(xiàn)時(shí)間和劑量依賴(lài)性;(6)鞘內(nèi)注射p65 sh RNA慢病毒能顯著緩解骨癌大鼠的痛敏行為,降低ATP誘發(fā)的電流,減少ATP誘發(fā)的動(dòng)作電位個(gè)數(shù)。4.小結(jié)以上結(jié)果提示P2X3R和p65均參與了癌細(xì)胞誘導(dǎo)的骨癌大鼠痛覺(jué)過(guò)敏的發(fā)生發(fā)展,且P2X3R的功能受到了p65的調(diào)控。第二部分:研究NF-κB參與P2X3R表達(dá)調(diào)控的分子及表觀遺傳學(xué)機(jī)制1.研究目的(1)分析NF-κB p65和P2X3R兩者表達(dá)的相關(guān)性,檢測(cè)其是否共定位于大鼠脛骨特異性DRG神經(jīng)元中;(2)檢測(cè)p65特異性抑制劑或LV-p65 sh RNA沉默p65表達(dá)是否可以抑制P2X3R表達(dá);(3)生物學(xué)軟件預(yù)測(cè)p2x3r基因啟動(dòng)子區(qū)Cp G島上可能存在的p65結(jié)合位點(diǎn),并進(jìn)一步用染色質(zhì)免疫共沉淀法(Ch IP)進(jìn)行驗(yàn)證;(4)檢測(cè)p2x3r基因啟動(dòng)子區(qū)Cp G島的DNA甲基化情況,探討甲基化狀態(tài)的改變對(duì)p65與其結(jié)合的影響;(5)初步探討p2x3r基因啟動(dòng)子區(qū)Cp G島甲基化狀態(tài)發(fā)生改變的機(jī)制,即檢測(cè)骨癌大鼠脛骨相關(guān)的DRG中主動(dòng)去甲基化相關(guān)的蛋白MBD2,MBD4,Gadd45a,TDG以及被動(dòng)去甲基化的DNA甲基化轉(zhuǎn)移酶DNMT3a和DNMT3b表達(dá)變化情況。2.實(shí)驗(yàn)方法(1)應(yīng)用統(tǒng)計(jì)學(xué)分析p65和P2X3R兩者的表達(dá)是否存在相關(guān)性。用免疫熒光染色檢測(cè)p65與P2X3R在脛骨特異性DRG神經(jīng)元上的共定位情況;(2)檢測(cè)p65抑制劑PDTC或p65 sh RNA慢病毒能否逆轉(zhuǎn)P2X3R的高表達(dá),以進(jìn)一步驗(yàn)證p65是否調(diào)控P2X3R表達(dá);(3)應(yīng)用生物學(xué)軟件Gene regulation(alibaba2)在線(xiàn)預(yù)測(cè)p2x3r基因啟動(dòng)子區(qū)Cp G島上的p65結(jié)合位點(diǎn),用染色質(zhì)免疫沉淀法(Ch IP)進(jìn)一步驗(yàn)證;(4)應(yīng)用MSP(甲基化特異性PCR)和BSP(重亞硫酸氫鹽測(cè)序PCR)檢測(cè)大鼠脛骨相關(guān)的DRG中p2x3r基因啟動(dòng)子區(qū)的甲基化情況;(5)應(yīng)用Real-time PCR方法檢測(cè)大鼠脛骨相關(guān)的DRG中DNMT3a,DNMT3b,Gadd45a,MBD2,MBD4和TDG的表達(dá)情況。3.實(shí)驗(yàn)結(jié)果(1)在骨癌痛模型大鼠脛骨相關(guān)的DRG中p65和P2X3R兩者表達(dá)呈相關(guān)性;p65與P2X3R共表達(dá)于大鼠脛骨特異性DRG神經(jīng)元中;(2)p65抑制劑PDTC或p65 sh RNA慢病毒能顯著抑制骨癌大鼠脛骨相關(guān)的DRG中P2X3R的表達(dá);(3)在線(xiàn)軟件預(yù)測(cè)p2x3r基因啟動(dòng)子區(qū)Cp G島上存在5個(gè)p65結(jié)合位點(diǎn),染色質(zhì)免疫沉淀法(Ch IP)檢測(cè)顯示p65與Cp G島上1,4和5這三個(gè)位點(diǎn)均有結(jié)合,且在第1位點(diǎn)上骨癌痛組結(jié)合顯著增強(qiáng);(4)骨癌痛大鼠脛骨相關(guān)的DRG中p2x3r基因啟動(dòng)子區(qū)Cp G島發(fā)生明顯的去甲基化;(5)骨癌大鼠脛骨相關(guān)的DRG中DNMT3a和DNMT3b表達(dá)水平顯著降低,但Gadd45a,MBD2,MBD4和TDG的表達(dá)沒(méi)有發(fā)生顯著變化。4.小結(jié)癌細(xì)胞注射引起的大鼠脛骨相關(guān)DRG中的P2X3R高表達(dá)可能是由于其啟動(dòng)子區(qū)Cp G島去甲基化增強(qiáng)進(jìn)以及與p65結(jié)合增加導(dǎo)致的;p2x3r基因啟動(dòng)子區(qū)Cp G島上去甲基化可能是由于DNMT3a和DNMT3b表達(dá)下降所致,這些結(jié)果提示DNA甲基化參與調(diào)控骨癌痛的發(fā)生發(fā)展。結(jié)論(1)癌細(xì)胞注射引起p2x3r基因啟動(dòng)子區(qū)DNA去甲基化增強(qiáng)以及與p65結(jié)合增加,導(dǎo)致P2X3R表達(dá)增加,ATP電流增強(qiáng),從而產(chǎn)生骨癌大鼠痛覺(jué)過(guò)敏;(2)DNMT3A和DNMT3B表達(dá)下降可能是引起p2x3r基因啟動(dòng)子DNA去甲基化原因之一,提示表觀調(diào)控參與骨癌痛發(fā)生發(fā)展;(3)P2X3R和p65參與骨癌痛的形成,提示P2X3R和p65可以作為治療骨癌痛的潛在靶點(diǎn)。
[Abstract]:Bone cancer pain caused by primary bone tumor or metastatic tumor is a serious and stubborn pain, which seriously affects or damages the functional status, life quality and life time of the patients. At present, the molecular mechanism of bone pain is still unclear and effective clinical treatment is limited. Therefore, it is urgent to further explore the occurrence of bone cancer pain. The molecular mechanism of the exhibition is to find new therapeutic targets. Recent studies have found that the destruction of the bone and the inflammation caused by acidosis, the products released by the tumor, the fracture caused by the tumor, the local ischemia, the invasion of the tumor and so on can cause the pain of bone cancer. Methotrexate receptor P2X3R plays an important role in the development of inflammatory pain, neuropathic pain and visceral pain, but there is little study on its function and expression regulation mechanism in bone cancer pain. In the process of bone cancer pain formation, tumor cells and stromal cells secrete some proinflammatory factors to sensitize the peripheral primary afferent nerve. The expression of inflammatory related factors in neurons is increased, and NF- kappa B is an important regulatory factor of inflammation, and it is widely involved in inflammation and regulation of the expression of pain related genes. However, whether NF- kappa B is involved in the regulation of P2X3R is still unclear during the process of bone cancer pain. Therefore, we will discuss the regulation of P2X3R from the epigenetic angle. Characteristics and the characteristics of NF- kappa B to seek new targets for the treatment of bone cancer pain and provide a theoretical basis for clinical treatment of bone cancer pain. Part 1: study the 1. research purposes of whether P2X3R and NF- kappa B participate in the development of bone cancer pain (1) detection of hyperalgesia and related electrophysiological mechanisms in the rat model of bone cancer; (2) the study of whether P2X3R is a reference. And the development of bone cancer pain; (3) to explore the mechanism of NF- kappa B mediated rat bone cancer pain mechanism.2. experimental method (1) the experimental study subjects were female adult rats. The rat model of bone cancer pain was established by injecting Walker 256 cells (4 x 105) into the bone marrow cavity of the tibia of the rat breast cancer. The X ray imaging and histomorphological examination were used. The morphological changes of the tibia were measured to verify the success of the model. Von Frey filament (VFF) and TSPS were used to detect the mechanical pain threshold and thermal pain threshold, and the bipedal balance instrument was used to detect the difference of bipedal balance to evaluate the hyperalgesia induced by bone cancer. (2) the Di I retrograde tracer was used to control the specific DRG neurons of the tibia in rats; (3) Real- Time PCR and Western blotting methods were used to detect the expression of Rel B, p52, p65 p-p65, and purine receptor of the members of the NF- kappa B family associated with the tibia of the rat tibia; (4) detection of the current of the rat tibial specific neurons by the whole cell patch clamp technique; (5) the detection of the purinergic receptor. Whether inhibitor Suramin or P2X3R and P2X2/3R strong inhibitor A317491 can reverse the pain sensitivity of bone cancer rats to determine whether P2X3R participates in the occurrence of bone cancer pain; (6) detection of p65 inhibitor PDTC or BAY-11-7082 can reverse the pain sensitivity of bone cancer rats to determine whether p65 participates in the formation of bone cancer pain; (7) detection of intrathecal p65 sh RNA lentivirus reduces tibia Specific neuronal excitability and bone cancer pain sensitivity, further determine whether p65 participates in the formation of bone cancer pain in.3. experimental results (1) after two weeks of injection of breast cancer cells, X ray imaging and morphological observation of bone carcinomas in bone cancer rats are obviously damaged, and the bone marrow cavity of the tibia is filled with a large number of cancer cells; behavior detection shows that the bone cancer rats are produced. There were obvious hyperalgesia; (2) the tibial specific neurons dominated by Di I marked by fluorescence retrograde tracer were mainly distributed in the DRG of the 4 segments of the lumbar segment L2-L5. (3) electrophysiological tests found that the ATP current of the tibial specific DRG neurons of the bone cancer rats increased significantly after two weeks of injection of the tumor cells, and the ATP induced by ATP. The number of action potential increased significantly; (4) the expression of P2X3R in the tibial related DRG of rats was significantly up-regulated after two weeks of injection of cancer cells. Intrathecal injection of purinergic receptor inhibitor Suramin, P2X3R and P2X2/3R strong inhibitor A317491 could significantly alleviate the hyperalgesia of bone cancer rats. The effect was time and dose dependent; (5) two cancer cells were injected. The expression of p65 and phosphorylated p65 in the tibial related DRG was significantly increased after the week, and the p65 inhibitor PDTC or BAY-11-7082 could significantly reduce the hyperalgesia of the bone cancer rats. The remission effect showed time and dose dependence. (6) intrathecal p65 sh RNA lentivirus could significantly alleviate the pain sensitivity of the bone cancer rats, reduce the current induced by ATP, and reduce the current induced by ATP. The results of a few ATP induced action potential number.4. indicated that both P2X3R and p65 were involved in the development of hyperalgesia induced by cancer cells, and the function of P2X3R was regulated by p65. The second part: the study of the molecular and epigenetic mechanism of NF- kappa B involved in the regulation of P2X3R expression and the mechanism of apparent relic study (1) analysis of NF- kappa B p65 and exports The correlation of the expression of X3R and whether it is located in the rat tibial specific DRG neurons; (2) whether the p65 specific inhibitor or the silent p65 expression of LV-p65 sh RNA can inhibit the expression of P2X3R; (3) biological software predicts the possible presence of the p65 binding site on Cp G island of the p2x3r promoter region, and further uses chromatin free The pestilence coprecipitation method (Ch IP) was used to verify, (4) to detect the DNA methylation of Cp G island in the promoter region of the p2x3r gene, and to explore the influence of the methylation status on the p65 and its binding; (5) the mechanism of the alteration of the methylation status of Cp G island in the promoter region of p2x3r gene was preliminarily discussed, that is to detect the active demethylation phase of the tibia related DRG in the bone cancer rat Protein MBD2, MBD4, Gadd45a, TDG, and DNA methylation transferase DNMT3a and DNMT3b expression changes in passive demethylation.2. experimental method (1) statistical analysis of the correlation between the expression of both p65 and P2X3R. The co localization of p65 and P2X3R in the tibial specific neuron was detected by immunofluorescence staining; (2) detection of the expression of p65 and P2X3R on the tibial specific neuron. Whether the p65 inhibitor PDTC or p65 sh RNA lentivirus can reverse the high expression of P2X3R, to further verify whether p65 regulates P2X3R expression; (3) the application of the biological software Gene regulation (alibaba2) to predict the binding site on the p2x3r gene promoter on line, further verified by the chromatin immunoprecipitation method; (4) application of methyl methylene (methyl) The methylation of the p2x3r gene promoter region in the tibial associated DRG of rats was detected by chemical specific PCR) and BSP (heavy hydrogen sulfite sequencing PCR). (5) the Real-time PCR method was used to detect DNMT3a, DNMT3b, Gadd45a, MBD2, Gadd45a, and expression in the tibial associated DRG of rats (1) in the tibial associated rat model of bone cancer pain model The expression of both p65 and P2X3R was correlated; p65 and P2X3R were co expressed in the specific DRG neurons of the tibia of rats; (2) p65 inhibitor PDTC or p65 sh RNA lentivirus could significantly inhibit the expression of P2X3R in the DRG of the tibia associated with bone cancer rats; (3) the online software predicted that there were 5 binding sites on the island of the promoter region of the gene, and the chromatin immunity was immunized. Ch IP detection showed that p65 was combined with 1,4 and 5 on Cp G Island, and the combination of bone cancer pain group was significantly enhanced at the first site. (4) the Cp G island of the p2x3r gene promoter region of the tibial associated DRG of the bone cancer rats was obviously demethated; (5) the level of DNMT3a and expression in the tibia associated DRG of bone cancer rats decreased significantly. Low, but the expression of Gadd45a, MBD2, MBD4 and TDG did not change significantly. The high expression of P2X3R in the tibial associated DRG induced by.4. nodule injection may be due to the enhancement of the Cp G Island demethylation in the promoter region and the increase of p65 binding with p65. The results showed that the expression of NMT3b was reduced. These results suggest that DNA methylation participates in the regulation of the development of bone cancer pain. Conclusion (1) the enhancement of DNA demethylation in the promoter region of the p2x3r gene and the increase of the binding with p65 lead to the increase of P2X3R expression and the increase of the ATP current, resulting in the hyperalgesia of the bone cancer rats, and (2) the decrease of DNMT3A and DNMT3B expression. It may be one of the causes of p2x3r gene promoter DNA demethylation, suggesting that apparent regulation participates in the development of bone cancer pain; (3) P2X3R and p65 are involved in the formation of bone cancer pain, suggesting that P2X3R and p65 can be used as potential targets for the treatment of bone cancer pain.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R730

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