短肽涂层抑制稀土纳米颗粒诱发炎症小体活化效应的研究

发布时间：2018-03-06 06:52

本文选题：稀土纳米材料　切入点：NLRP3炎症小体　出处：《中国科学技术大学》2016年博士论文　论文类型：学位论文

【摘要】：稀土元素是指化学周期表中的镧系15种元素以及钪、钇共17种元素的总称。由于优异的光、电、磁特性,稀土材料被广泛应用于陶瓷、发光材料、永磁材料、环保材料、催化剂材料以及信息科学和生物医学等领域。稀土上转换发光纳米材料作为一种新型标记生物材料,具有良好的生物相容性,在生物载药、成像、检测、即时诊断器件开发等生物医学工程中已被广泛应用。然而,同其他纳米材料一样,稀土纳米材料在方便人们生活的同时也面临着亟待解决的生物安全性问题。最近的研究表明稀土纳米颗粒会在巨噬细胞中激活NLRP3炎症小体,促进活化的caspase-1和成熟的IL-1p分泌到胞外,引起caspase-1依赖的细胞焦亡。NLRP3炎症小体的活化参与多种炎症性疾病的发生与发展,包括Ⅱ型糖尿病,动脉粥样硬化,痛风,阿尔兹海默症等重大疾病。RE-1是2012年用噬菌体展示技术发现的一条特异性结合稀土纳米材料的短肽,本研究用RE-1涂层稀土纳米颗粒能降低其在巨噬细胞中诱发的NLRP3炎症小体的活化并能减少稀土纳米材料的体内炎症效应。与之前发现的RE-1降低稀土纳米颗粒与Hela细胞的相互作用不同,RE-1涂层并不影响稀土纳米颗粒物进入巨噬细胞。另外,RE-1涂层不能抑制稀土纳米颗粒诱发的钾离子外泄,但会部分抑制稀土纳米颗粒导致的巨噬细胞溶酶体损伤,但蛋白酶cathepsinB的抑制剂预处理细胞并不能减少稀土纳米颗粒引发的炎症小体的活化。稀土纳米颗粒会在巨噬细胞中诱发ROS的产生,ROS会活化TRPM2导致Ca2+内流增加细胞内钙离子浓度,进而活化NLRP3炎症小体。而RE-1涂层会抑制稀土纳米颗粒物产生ROS,抑制Ca2+内流,抑制NLRP3炎症小体的活化。并且,RE-1涂层主要抑制稀土纳米颗粒物活化NADPH氧化酶产生ROS而对线粒体呼吸链产生的ROS没有明显的抑制作用。本研究提供了一种通过表面涂层特异性结合肽减少稀土纳米材料的炎症反应,提高其生物安全性的修饰方法,这对于稀土纳米材料以及其他工程性纳米材料的体内应用具有重大意义。
[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.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R96

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