發(fā)布時間：2018-05-10 07:35

  本文選題：脊髓損傷 + 納米微球��； 參考：《浙江大學(xué)》2017年博士論文

【摘要】：脊髓損傷(SCI)是最具毀滅性的創(chuàng)傷之一,目前的處理獲得功能恢復(fù)非常有限。SCI給每一位患者的家庭和社會都帶來了沉重的負(fù)擔(dān),探尋其療法非常重要。SCI后,損傷局部遭受嚴(yán)重的炎癥反應(yīng)。炎癥因子與SCI修復(fù)密切相關(guān),其中許多因子已被證明可以直接促進(jìn)或者抑制SCI修復(fù)。大鼠SCI之后局部炎癥因子蛋白水平的程序性變化卻并未得到解析。故我們在第一章以大鼠為模型研究損傷脊髓局部微環(huán)境的炎癥因子程序性變化。我們發(fā)現(xiàn)大鼠SCI后7個可能利于和11個可能阻礙SCI修復(fù)的炎癥因子在損傷后有差異性的變化。其中,4個利于SCI修復(fù)的炎癥因子水平在損傷后下降,9個阻礙SCI修復(fù)的炎癥因子水平在損傷后升高。這為后期臨床前研究中針對SCI藥物篩查,和臨床上的治療和預(yù)后提供了基礎(chǔ)生物學(xué)數(shù)據(jù)。SCI后細(xì)胞周期病理性激活,不僅導(dǎo)致神經(jīng)元和少突膠質(zhì)細(xì)胞死亡,且引起小膠質(zhì)細(xì)胞、星形膠質(zhì)細(xì)胞及其前體細(xì)胞的增殖和激活。有研究發(fā)現(xiàn),夫拉平度在大鼠SCI后減少病灶體積和星形膠質(zhì)細(xì)胞的增殖,降低神經(jīng)元和少突膠質(zhì)細(xì)胞的凋亡,促進(jìn)了運(yùn)動功能的恢復(fù)。而星形膠質(zhì)細(xì)胞是重要的炎癥因子來源。故第二章探究夫拉平度是否能夠抑制星形膠質(zhì)細(xì)胞炎癥因子的合成。我們發(fā)現(xiàn),夫拉平度抑制星形膠質(zhì)細(xì)胞的炎癥因子合成、增殖和劃痕愈合,且不影響神經(jīng)元的存活,提示其很可能可以促進(jìn)SCI修復(fù)。在SCI研究中,夫拉平度現(xiàn)有的兩種給藥方式都有缺憾:全身性高劑量給藥有副作用;緩釋微泵鞘內(nèi)給藥成本較高,且有組織相容性風(fēng)險。有研究在大鼠SCI中發(fā)現(xiàn),甲強(qiáng)龍PLGA納米微球局部給藥比全身性給藥更有效。故我們在第三章制作夫拉平度PLGA微球局部緩釋制劑,并研究其對SCI修復(fù)的效果。結(jié)果表明,合成的夫拉平度微球有長達(dá)三天的緩釋。夫拉平度微球明顯減少了星形膠質(zhì)細(xì)胞的促炎因子合成,同時提高了 IL-10合成。在體內(nèi),夫拉平度微球減少了星形膠質(zhì)細(xì)胞、神經(jīng)元和巨噬細(xì)胞的細(xì)胞周期相關(guān)蛋白的表達(dá),提高了脊髓大體組織結(jié)構(gòu)的完整性,降低了膠質(zhì)瘢痕和脊髓空洞形成,同時促進(jìn)了神經(jīng)的存活和再生。夫拉平度微球在損傷點提高了 GM-CSF蛋白水平,降低了 IP-10水平。最終,夫拉平度微球也促進(jìn)了 SCI大鼠的運(yùn)動功能恢復(fù)�？傊�,通過PLGA微球局部釋放夫拉平度通過調(diào)控局部星形膠質(zhì)細(xì)胞和炎癥反應(yīng)促進(jìn)了脊髓損傷的修復(fù)。我們的研究展示了通過PLGA微球局部緩釋夫拉平度的方法,提示SCI后促進(jìn)功能恢復(fù)的潛在臨床應(yīng)用前景。
[Abstract]:Sci (spinal cord injury) is one of the most devastating injuries. The recovery of the current treatment is very limited. Sci imposes a heavy burden on the family and society of every patient. After exploring the treatment of sci, it is very important. The local injury suffers from severe inflammatory reactions. Inflammatory factors are closely related to SCI repair, many of which have been shown to directly promote or inhibit SCI repair. The procedural changes in local inflammatory factor protein levels after SCI in rats were not analyzed. In Chapter 1, we used the rat model to study the programmed changes of inflammatory cytokines in the local microenvironment of spinal cord injury. We found that there were different changes in 7 and 11 inflammatory factors after SCI. Four of the inflammatory cytokines that were conducive to SCI repair decreased after injury, and 9 that hindered SCI repair increased after injury. This provides basic biological data for the screening of SCI drugs, clinical treatment and prognosis in the later preclinical study. The pathological activation of cell cycle after sci not only leads to the death of neurons and oligodendrocytes, but also to microglia. Proliferation and activation of astrocytes and their precursors. It has been found that fluapine reduces the volume of focus and the proliferation of astrocytes and the apoptosis of neurons and oligodendrocytes after SCI in rats and promotes the recovery of motor function. Astrocytes are an important source of inflammatory cytokines. The second chapter is to investigate whether Flappine can inhibit the synthesis of astrocytic inflammatory factors. We found that flapidium inhibits the synthesis of inflammatory cytokines proliferation and scratch healing of astrocytes and does not affect the survival of neurons suggesting that it may promote SCI repair. In the SCI study, there are two existing methods of administration of Fraphidu: systemic high dose administration has side effects, and sustained release micropump intrathecal delivery cost is high, and there is a risk of histocompatibility. Some studies have found that methylenolone PLGA nanoparticles are more effective in local administration than systemic administration in rat SCI. Therefore, in chapter 3, we prepared the local sustained release preparation of PLGA microspheres, and studied its effect on SCI repair. The results showed that the synthesized microspheres had sustained release for up to three days. Flampindu microspheres significantly reduced the pro-inflammatory factor synthesis of astrocytes and increased IL-10 synthesis. In vivo, Flampindu microspheres reduced the expression of cell cycle related proteins in astrocytes, neurons and macrophages, increased the integrity of the gross structure of the spinal cord, and reduced the formation of glial scars and syringomyelia. It also promotes nerve survival and regeneration. The level of GM-CSF protein was increased and the level of IP-10 was decreased at the point of injury. In the end, the flattened microspheres also promoted the recovery of motor function in SCI rats. In conclusion, the local release of flapidium through PLGA microspheres promotes the repair of spinal cord injury by regulating local astrocytes and inflammatory responses. Our study demonstrated the method of local sustained release of PLGA microspheres and suggested the potential clinical application of promoting functional recovery after SCI.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R651.2

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相關(guān)期刊論文 前3條

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本文編號：1868427