海南产疣缟芋螺毒素基因的多样性研究

The venom of tropical carnivorous marine snails from cone snails (genus Conus) provides a valuable source of biologically active peptides, which is a rich pharmaceutical treasure. The venom of each cone snail species is composed of a complex mixture of disulfide-rich ion channel neurotoxins, commonly known as conopeptides or conotoxins (CTXs), many of which target various ion-channels and receptors both the central and peripheral nervous system. Conotoxins blocked different ion channels in cell membranes with outstanding curative effects in addiction, anaesthesia, analgesic, cardiovascular disorders and neuropsychiatric disorders without addictive side effects. This natural library of bioactive peptides thus provides a rich source of potential drug leads or neurophysiological probes. These predatory marine snails live in South China Sea with various species native to Hainan. Every Conus species appears to have a repertoire of ~2000 different venom components, most of which are rare content. There are at least 50000 Hainan conopeptides are a real pharmaceutical cornucopia waiting to be tapped. Conotoxins, to date, only a small fraction (<0.1%) of these conotoxins have been identified and functionally characterized. Basic research of Hainan cone snails and conotoxins are weak. Furthermore most of the venom components are of very low concentration and the isolation/characterization of the conopeptide is vastly more difficult and the early conopeptide research in particular was limited to larger and more common Hainan Conus species. Fulfilling Hainan conotoxin resources research potential and efficiency depends on the steady discovery of new conotoxins. This multidisciplinary research project would focus on venom transcriptome, novel toxin gene discovery in large scale, and diversity of conotoxin genes of Conus lividus native to Hainan by functional genomics technology. C. lividus phylogeny and its toxin gene expression level, annotation and signal transmission, etc will be analyzed on the genome and venom transcriptome levels. The results would be the basis for new conotoxin synthesis，function identification, being developed as potent drugs, and benefit halobios resources contest of China.

被誉为海洋药物宝库的热带特有药用海洋生物芋螺分泌产生的毒素，具有特异结合动物体内各种离子通道和受体的功能，其结构新颖，选择性高，有很好的成药性，在成瘾、麻醉、镇痛和研究治疗神经和心脏疾病等方面具有极好的应用前景，已成为神经科学研究和新药研发的新来源。在我国，芋螺是海南特有的海洋生物。芋螺毒素的多样性极高，每种芋螺毒液中有近2000种不同的毒素肽，有约5万种海南产芋螺毒素急待开发。目前，海南产芋螺及其毒素的基础研究较薄弱，严重限制了新芋螺毒素的发现及其药用开发。本项目拟利用现代功能基因组学的技术手段，对代表性海南产疣缟芋螺毒液的转录组、毒素基因多样性进行系统研究，大量发现毒素新基因，在疣缟芋螺基因组与毒液转录组水平上进行物种进化关系、基因表达水平分析、基因注释、信号传导的途径分析等。研究成果将为更多芋螺毒素的人工合成、功能研究、疣缟芋螺分子分类、以及新药研发提供生物材料和前期基础工作。

被誉为海洋药物宝库的热带特有药用海洋生物芋螺分泌产生的毒素，具有特异结合动物体内各种离子通道和受体的功能，其结构新颖，选择性高，成药性好。芋螺毒素在研究治疗神经痛、成瘾、神经系统疾病、癌症和心脏疾病等诸多疑难杂症方面具有极好的应用前景，已成为神经科学研究和新药研发的新来源。在我国，芋螺是海南特有的海洋生物。芋螺毒素的多样性极高，每种芋螺毒液中有3000种不同的毒素肽，有约15万种海南产芋螺毒素急待开发。目前，海南产芋螺及其毒素的基础研究较薄弱，严重限制了新芋螺毒素的发现及其药用开发。本项目利用现代功能基因组学的技术手段，对代表性海南产疣缟芋螺毒液的转录组、毒素基因多样性进行了系统研究，大量发现毒素新基因，对疣缟芋螺及其毒素基因的多样性、进化关系等，进行了系统深入的分析。该研究成果将为更多芋螺毒素的人工合成、功能研究、疣缟芋螺分子分类、以及新药研发提供生物材料和前期基础工作。本项目远远超额完成了预期研究成果，先后在《J Med Chem》，《J Biol Chem》，《FASEB J》，《Neuropharmacology》，《Progress in Neuro-Psychopharmacology and Biological Psychiatry》, 《Scientific Reports》,《Marine Drugs》等期刊上发表论文33篇；培养研究生6名，其中博士2名，硕士4名。国际会议论文3篇；新申请专利3项，其中国家发明专利2项，国际PCT专利1项；新增专利授权2项，其中美国专利1项，中国发明专利1项。