本文選題：稀土納米材料　切入點(diǎn)：NLRP3炎癥小體　出處：《中國科學(xué)技術(shù)大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：稀土元素是指化學(xué)周期表中的鑭系15種元素以及鈧、釔共17種元素的總稱。由于優(yōu)異的光、電、磁特性,稀土材料被廣泛應(yīng)用于陶瓷、發(fā)光材料、永磁材料、環(huán)保材料、催化劑材料以及信息科學(xué)和生物醫(yī)學(xué)等領(lǐng)域。稀土上轉(zhuǎn)換發(fā)光納米材料作為一種新型標(biāo)記生物材料,具有良好的生物相容性,在生物載藥、成像、檢測、即時診斷器件開發(fā)等生物醫(yī)學(xué)工程中已被廣泛應(yīng)用。然而,同其他納米材料一樣,稀土納米材料在方便人們生活的同時也面臨著亟待解決的生物安全性問題。最近的研究表明稀土納米顆粒會在巨噬細(xì)胞中激活NLRP3炎癥小體,促進(jìn)活化的caspase-1和成熟的IL-1p分泌到胞外,引起caspase-1依賴的細(xì)胞焦亡。NLRP3炎癥小體的活化參與多種炎癥性疾病的發(fā)生與發(fā)展,包括Ⅱ型糖尿病,動脈粥樣硬化,痛風(fēng),阿爾茲海默癥等重大疾病。RE-1是2012年用噬菌體展示技術(shù)發(fā)現(xiàn)的一條特異性結(jié)合稀土納米材料的短肽,本研究用RE-1涂層稀土納米顆粒能降低其在巨噬細(xì)胞中誘發(fā)的NLRP3炎癥小體的活化并能減少稀土納米材料的體內(nèi)炎癥效應(yīng)。與之前發(fā)現(xiàn)的RE-1降低稀土納米顆粒與Hela細(xì)胞的相互作用不同,RE-1涂層并不影響稀土納米顆粒物進(jìn)入巨噬細(xì)胞。另外,RE-1涂層不能抑制稀土納米顆粒誘發(fā)的鉀離子外泄,但會部分抑制稀土納米顆粒導(dǎo)致的巨噬細(xì)胞溶酶體損傷,但蛋白酶cathepsinB的抑制劑預(yù)處理細(xì)胞并不能減少稀土納米顆粒引發(fā)的炎癥小體的活化。稀土納米顆粒會在巨噬細(xì)胞中誘發(fā)ROS的產(chǎn)生,ROS會活化TRPM2導(dǎo)致Ca2+內(nèi)流增加細(xì)胞內(nèi)鈣離子濃度,進(jìn)而活化NLRP3炎癥小體。而RE-1涂層會抑制稀土納米顆粒物產(chǎn)生ROS,抑制Ca2+內(nèi)流,抑制NLRP3炎癥小體的活化。并且,RE-1涂層主要抑制稀土納米顆粒物活化NADPH氧化酶產(chǎn)生ROS而對線粒體呼吸鏈產(chǎn)生的ROS沒有明顯的抑制作用。本研究提供了一種通過表面涂層特異性結(jié)合肽減少稀土納米材料的炎癥反應(yīng),提高其生物安全性的修飾方法,這對于稀土納米材料以及其他工程性納米材料的體內(nèi)應(yīng)用具有重大意義。
[Abstract]:Rare earth elements refer to 15 lanthanide elements in the periodic table and 17 elements of scandium and yttrium. Due to their excellent optical, electrical and magnetic properties, rare earth materials are widely used in ceramics, luminescent materials, permanent magnetic materials and environmental protection materials. Rare-earth up-conversion luminescent nanomaterials, as a new type of biomaterials, have good biocompatibility, biocompatibility, drug loading, imaging, detection, and so on. Biomedical engineering, such as the development of instant diagnostic devices, has been widely used. However, like other nanomaterials, Rare earth nanomaterials not only facilitate people's lives but also face urgent biosafety problems. Recent studies have shown that rare earth nanoparticles activate NLRP3 inflammatory corpuscles in macrophages. Promoting the secretion of activated caspase-1 and mature IL-1p to the extracellular, the activation of the caspase-1 dependent inflammatory corpuscles, NLRP3, is involved in the occurrence and development of many inflammatory diseases, including type 2 diabetes, atherosclerosis, gout. Major diseases, such as Alzheimer's disease. RE-1, a short peptide specifically bound to rare earth nanomaterials, was discovered in 2012 by phage display technology. In this study, RE-1 coated rare earth nanoparticles could reduce the activation of NLRP3 inflammatory bodies induced in macrophages and the inflammatory effect of rare earth nanomaterials in vivo. Compared with the previously discovered RE-1, rare earth nanoparticles and Hela fine particles could be reduced. In addition, RE-1 coating could not inhibit the release of potassium ions induced by rare earth nanoparticles. But it partially inhibits the lysosomal damage of macrophages caused by rare earth nanoparticles. However, inhibitor pretreatment of protease cathepsinB could not reduce the activation of inflammatory bodies induced by rare earth nanoparticles. Rare earth nanoparticles could induce the production of ROS in macrophages. Ros activated TRPM2 and Ca2 influx increased intracellular calcium concentration. In turn, NLRP3 inflammatory bodies are activated, and RE-1 coating inhibits the formation of ROSs by rare earth nanoparticles and inhibits the influx of Ca2. It inhibited the activation of NLRP3 inflammatory corpuscles, and the RE-1 coating mainly inhibited the activation of NADPH oxidase to produce ROS by rare earth nanoparticles, but had no obvious inhibition on ROS produced by mitochondrial respiratory chain. Coating-specific binding peptide reduces the inflammatory response of rare earth nanomaterials. It is of great significance for the in vivo application of rare earth nanomaterials and other engineering nanomaterials to improve their biological safety.
【學(xué)位授予單位】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R96

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本文編號：1573771