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题名	山羊cathelicidin抗菌肽的结构与功能初步研究
作者	杨雪宁
学位类别	硕士
答辩日期	2012-05
授予单位	中国科学院研究生院
授予地点	北京
导师	赖仞
关键词	山羊 cathelicidin 抗菌肽 结构 功能 动物模型
其他题名	Structure and Function Research of Goat Cathelicidin
学位专业	生物化学与分子生物学
中文摘要	Cathelicidin是最初从哺乳动物体内发现的具有多功能的抗菌肽家族，在先天免疫中起着重要作用。Cathelicidin家族一般结构都比较保守。Cathelicidin的N-端是保守的信号肽区和cathelin区，C-端是大小不一(12-100个氨基酸残基)的阳离子抗菌肽区。C-端从前体蛋白中释放之后变成活性状态。很多cathelicidin抗菌肽具有广谱的抗微生物活性，不但对普通革兰氏阳性细菌、革兰氏阴性细菌、真菌以及病毒具有活性，而且对许多临床耐药微生物同样具有作用。cathelicidin还具有许多其他生物学活性，如对多种免疫细胞具有趋化作用、诱导肥大细胞脱粒和组织胺释放、调节巨噬细胞转录、促进伤口愈合、诱导血管发生、诱导变异细胞系细胞凋亡和淋巴细胞活化等。 在本论文中，我们对山羊来源的cathelicidin抗菌肽(GC)进行了一系列研究。首先，我们对GC的结构进行了分析。预测并合成了成熟肽区域。对GC可能具有的一些生物学活性进行了研究。GC对革兰氏阴性细菌和白色念珠菌具有很好的抗菌活性，其中包括大量临床分离耐药菌株，对革兰氏阳性菌活性不明显。GC可以清除ABTS+自由基。GC的溶血活性、凝集素活性和丝氨酸蛋白酶抑制剂活性均不明显。杀菌动力学，圆二色谱和扫描电子显微镜等实验结果表明，GC可能是通过结合到微生物细胞质膜上，诱导其构象发生改变，导致微生物细胞膜内陷，最终在膜上形成孔洞，引起细胞内容物外泄，导致微生物死亡。 通过体外和体内实验对GC进行了初步的药理学和药效学研究。GC在血清中稳定性较好。一定浓度的盐离子能够增强GC的抗菌活性。实验动物模型研究表明，GC对白色念珠菌引起的小鼠阴道炎感染具有很好的治疗效果。GC本身所具有的特点及在动物模型实验中表现出的治疗效果使其成为抗菌药物开发的优良模板。
英文摘要	Cathelicidins are a family of antimicrobial peptides acting as multifunctional effector molecules of innate immunity, which are firstly found in mammalians. Cathelicidins have conserved structures. Cathelicidins consist of an N-terminal putative signal peptide, a conserved cathelin-like domain, and a C-terminal antimicrobial domain that varies remarkably in size (ranging from 12 to 100 amino acids) . C-terminal cationic antimicrobial domain that becomes active after being released from the N-terminal cathelin portion of the holoprotein. They possess broad spectrum antimicrobial activity, not only against Gram-positive bacteria, Gram-negtive bacteria, fungi, and viruses, but also many antibiotic-resisted clinical bacteria. In addition, they possess many other biological activities, such as immune cell chemotaxis, mast cell degranulation, and histamine release, transcriptional regulation of macrophages, wound repairing, angiogenesis, cytolytic activity, etc. In this thesis, a series of experiments were carried out to study goat cathelicidin (GC) antimicrobial peptide family from Capra hirca. We analyzed the structure of GC, predicted and synthesized the mature peptide. The possible biological activities of GC were invesitigated. It is microbicidal against Gram-negtive bacteria and fungi, including many antibiotic-resisted clinical bacteria, but not obvious to Gram-positive bacteria. GC had the activity to scavenge ABTS+ radical. GC exhibited no hemolytic activity, lectin-like activity, and serine protease inhibitory activity. According to the results of bacteria killing kinetics experiment, circular dichroism spectroscopy (CD) and scaning electron microscopy (SEM), we deduced that GC attached to microbial plasma membrane through electrostatic interaction, changed the conformation, leaded to microbial plasma membranes retraction and induced the death of bacteria cells. In vitro and in vivo experiments were carried out for pharmacological and pharmacodynamic study of GC. GC exhibited good stability in human normal serum. A certain concentration of salt could increased GC’s antimicrobial activity. Animal model experiments showed that GC possessed effective therapeutic effects against mice vaginitis infection induced by candida albicans. The characteristics of GC and its therapeutic efficacy demonstrated by animal model experiments make it an excellent template for the development of topical antibiotics.
语种	中文
公开日期	2012-06-07
内容类型	学位论文
源URL	[http://159.226.149.42:8088/handle/152453/6970]
专题	昆明动物研究所_动物毒素室
推荐引用方式 GB/T 7714	杨雪宁. 山羊cathelicidin抗菌肽的结构与功能初步研究[D]. 北京. 中国科学院研究生院. 2012.

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